1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols and related compounds

ABSTRACT

Novel 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, intermediates and processes for the preparation thereof, and methods of reducing inflammation and cell proliferation, and relieving memory dysfunction, and inhibiting bacterial and fungal growth are disclosed.

This is a division of prior application Ser. No. 07/942,908 filed Sep.10, 1992, now U.S. Pat. No. 5,360,811, which is a continuation-in-partof prior application Ser. No. 07/840,236 filed Feb. 24, 1992, nowabandoned, which is a continuation of prior application Ser. No.07/632,910 filed Dec. 24, 1990, now abandoned, which is acontinuation-in-part of prior application Ser. No. 07/596,448 filed Oct.12, 1990, now abandoned which is a continuation-in-part of applicationSer. No. 07/492,200 filed Mar. 13, 1990, now abandoned.

The present invention relates to 1-alkyl-, 1-alkenyl-, and1-alkynylaryl-2-amino-1,3-propanediols. More particularly, the presentinvention relates to 1-alkyl-, 1-alkenyl-, and1-alkylnylaryl-2-amino-1,3-propanediols of formula 1.

    RCH(OR.sup.1)CH(NR.sup.2 R.sup.3)R.sup.4 or RCH.sub.2 CR.sup.35 (NR.sup.2 R.sup.3)R.sup.4                                           1

wherein R is ##STR1## wherein R⁵ is CH₃ (CH₂)_(m) CΞC, CH₃ (CH₂)_(m)CH═CH, CH₃ (CH₂)_(m) CH₂ CH₂, ##STR2## wherein m is 3 to 15, n is 0 to12, and W and X are independently hydrogen, hydroxy, alkyl, alkoxy,halogen, or trifluoromethyl, or ##STR3## wherein R²³ is loweralkyl; Z isS, O, or C═O; and A is S or O; R¹ is hydrogen, alkyl, Si(R²³)₂ C(R²³)₃wherein R²³ is alkyl, ##STR4## wherein R²⁴ isalkyl or ##STR5## whereinR⁶ is hydrogen, alkyl, alkoxy, N(R²¹)₂ wherein R²¹ is hydrogen, alkyl,or ##STR6## wherein W is as above, or ##STR7## R² is hydrogen or alkyl;R³ is hydrogen, alkyl or ##STR8## wherein R⁶ is as above or NHR²⁷wherein R²⁷ is alkyl; R³⁵ is ##STR9## wherein R³⁶ is alkyl; R⁴ is##STR10## wherein R⁷ is hydrogen or alkyl, C(R²⁵)₂ OR⁸ wherein R⁸ ishydrogen, alkyl, or ##STR11## wherein R⁶ is as above and R²⁵ is hydrogenor alkyl; R⁴⁰ is alkyl or a group of the formula ##STR12## wherein W isas above; R¹ and R⁸ taken together with the oxygen to which they areattached form a group of the formula ##STR13## wherein R⁹ and R¹⁰ areindependently hydrogen or alkyl; R², R³ and R⁴ taken together with thenitrogen and oxygen to which they are attached form a group of theformula ##STR14## wherein W is as above; R₃ and R₄ taken together withthe nitrogen and oxygen atoms to which they are attached form a group ofthe formula ##STR15## wherein R² is as above; R² and R³ taken togetherwith the nitrogen atom to which it is attached form a group of theformula ##STR16## wherein W is as above; R³ and R⁴ taken together withthe nitrogen and oxygen atoms to which they are attached form a group ofthe formula ##STR17## wherein R² is as above and R²⁵ is alkyl; R¹, R²and R³ taken together with the nitrogen and oxygen atoms to which theyare attached form a group of the formula ##STR18## wherein R²⁶ is alkyl;the optical isomers thereof, or the pharmaceutically acceptable saltsthereof, which are useful for reducing inflammation by virtue of theirability to inhibit protein kinase C and thus indicated for the treatmentof psoriasis and other skin disorders, for inhibiting tumor orneoplastic cell growth by virtue of their ability to reduce cellproliferation and thus indicated in cancer therapy, and relieving memorydysfunction and thus indicated in the treatment of Alzheimer's disease,and as antibacterial and antifungal agents, alone or in combination withadjuvants.

Preferred 2-amino-1,3-propanediols of the present invention are thosewherein R is ##STR19## R¹, R², and R³ are hydrogen and R⁵ is CH₃(CH₂)_(m) CH₂ CH₂ or ##STR20## Also preferred are compounds wherein R is##STR21## R¹ and R² are hydrogen; R⁴ is ##STR22## and R⁵ is CH₃(CH₂)_(m) CΞC.

The present invention also relates to compounds of the formulas

    RCHO                                                       1a

wherein R is ##STR23## wherein R⁵ is CH₃ (CH₂)_(m) CΞC, CH₃ (CH₂)_(m)CH═CH, CH₃ (CH₂)_(m) CH₂ CH₂, or ##STR24## wherein m is 3 to 15, n is 0to 12, W and X are independently hydrogen, alkyl, alkoxy, halogen, ortrifluoromethyl and Z is S or O; A is S or O; R⁴⁰ is alkyl or a group ofthe formula ##STR25## wherein W is as above; ##STR26## wherein R is##STR27## wherein R⁵ is CH₃ (CH₂)_(m) CΞC, CH₃ (CH₂)_(m) CH═CH, CH₃(CH₂)_(m) CH₂ CH₂, or ##STR28## wherein m is 3 to 15, n is 0 to 12, R¹⁶is hydrogen or a group of the formula ##STR29## W and X areindependently hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, andZ is 0; and

    RCH═CHR.sup.4

wherein R is ##STR30## wherein R⁵ is CH₃ (CH₂)_(m) CΞC, CH₃ (CH₂)_(m)CH═CH, CH₃ (CH₂)_(m) CH₂ CH₂, ##STR31## wherein m is 3 to 15, n is 0 to12, and W and X are independently hydrogen, loweralkyl, loweralkoxy,halogen, or trifluoromethyl, Z is S, O, or C═O; and A is S or O, and R⁴is ##STR32## wherein R⁷ is hydrogen or loweralkyl, C(R²⁵)₂ OR⁸ whereinR⁸ is hydrogen, loweralkyl, or ##STR33## is as above; and ##STR34##wherein R⁵ is CH₃ (CH₂)_(m) CΞC, CH₃ (CH₂)_(m) CH═CH, CH₃ (CH₂)_(m) CH₂CH₂, ##STR35## wherein m is 3 to 15, n is 0 to 12, and W and X areindependently hydrogen, loweralkyl, loweralkoxy, halogen, ortrifluoromethyl which are useful as intermediates for the preparation ofthe present 2-amino-1,3-propanediols.

Also included as intermediates for the preparation of the present2-amino-1,3-propanediols are oxazolidinones of the formula

    RCH(OR.sup.1)CHR.sup.18 R.sup.19

wherein R is ##STR36## wherein R⁵ is CH₃ (CH₂)_(m) C.tbd.C, CH₃(CH₂)_(m) CH═CH, CH₃ (CH₂)_(m) CH₂ CH₂, ##STR37## wherein m is 3 to 25,n is 0 to 12, and W and X are independently hydrogen, alkyl, alkoxy,halogen, or trifluoromethyl, Z is S, O, or C═O; and A is S or O; R¹ ishydrogen or ##STR38## wherein R⁶ is hydrogen, alkyl, alkoxy, or##STR39## R¹⁸ is halogen or N₃ ; and R¹⁹ is a group of the formula##STR40## wherein W is hydrogen, loweralkyl, loweralkoxy, halogen, ortrifluoromethyl; or a group of the formula ##STR41## wherein R²⁰ isloweralkyl.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 10 carbon atoms. Examples of alkyl groupsare methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl,4-heptyl, 2-octyl, 3-nonyl, 4-decyl and the like. The term "alkanol"refers to a compound formed by a combination of an alkyl group andhydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol, decanol and the like.The term "alkanoic acid" refers to a compound formed by combination of acarboxyl group with a hydrogen atom or alkyl group. Examples of alkanoicacids are formic acid, acetic acid, propanoic acid, 2,2-dimethylaceticacid, hexanoic acid, octanoic acid, decanoic acid and the like. The term"halogen" refers to a member of the family fluorine, chlorine, bromine,or iodine. The term "alkanoyl" refers to the radical formed by removalof the hydroxyl function from an alkanoic acid. Examples of alkanoylgroups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl,octanoyl, decanoyl and the like. The term "lower" as applied to any ofthe aforementioned groups refers to a group having a carbon skeletoncontaining up to and including 8 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, those instant compounds characterized by the presence of acarboxylic acid group and an optically active base, or by synthesis fromoptically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof and all geometric isomers of the compounds disclosed and claimedherein. The formulas of the compounds shown herein are intended toencompass all possible geometric and optical isomers of the compounds sodepicted.

The compounds of the present invention that have adjacent chiral centersexist as diastereomers and are distinguished as the erythro- andthreo-isomers. The erythro diastereomers are those that become meso,i.e., optically inactive, by virtue of having an element of symmetry inone of the possible conformations, when one of the dissimilarsubstituents is replaced by the other. The threo diastereomers are thosethat remain enantiomeric, i.e., optically active, by virtue of lackingan element of symmetry in one of the possible conformations, when one ofthe dissimilar substitutents is replaced by the other. For example,replacement of the amino group of an erythro-2-amino-1,3-propanediol 9aof the present invention by a hydroxyl group creates ameso-1,2,3-propanetriol 9b, having a plane of symmetry through thecarbon backbone of the molecule, as shown below, ##STR42## andreplacement of the amino group of a threo-2-amino-1,3-propanediol 9c ofthe present invention by a hydroxy group creates an enantiomer 9d,lacking an element of symmetry in all conformations, one of which is 9d.##STR43##

The chirality of the enantiomeric compounds of the present invention,prepared by asymmetric induction, is designated by the symbols "R" and"S" and is determined by application of the sequence-rule ofCahn-Ingold- and Prelog (see R. S. Cahn, C. Ingold, and v. Prelog,Angewandte Chemie, International Edition English, 5, 385 (1966) and 5,511 (1966). Thus, for example, the handedness of the chiral centers atthe 2- and 3-positions of the 2-amino-1,3-propanediol 9e ##STR44##prepared from (4S)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, isdesignated 2R (right) and 3S (left). The centers of the enantiomeric2-amino-1,3-propanediol 9f, ##STR45## prepared from the enantiomeric(4R)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone, is designated 2Sand 3R.

The novel 1-alkyl-, 1-alkenyl-, and1-alkynylaryl-2-amino-1,3-propanediols of the present invention areprepared by the processes illustrated in Reaction Schemes A, B, and Cfor the pyridine series, D to L for the thiophene series, and M and Nfor the phenyl series, having an aralkyl side-chain. The transformationsshown therein are applicable to the preparation of compounds of theinvention wherein the aryl group is, among others, substituted andunsubstituted phenyl, furyl, thienyl, isoxazolyl, isothiazolyl, andpyrrolyl, thiazolyl, and oxazolyl, having a 1-alkyl, 1-alkenyl, or1-alkynyl-side chain.

To prepare a 1-alkynylpyridinyl-2-amino-1,3-propanediol 7 wherein W andX are hydrogen, alkyl, alkoxy, halogen, or trifluoromethyl, apyridinylcarboxaldehyde 2 wherein W and X are as above and Y is halogenis condensed with an amidomalonic acid ester 3 wherein R¹¹ and R¹² arealkyl to provide an alkyl pyridinylpropionate 4 wherein R¹¹, R¹², X, andY are as above, which is alkynylated to alkynylpyridine 5 wherein R¹¹,R¹², W and X are as above and n is 3 to 15 and, in turn, reduced topyridinyl-1,3-propanediol 6 wherein R¹², W, and X are as above andhydrolyzed to 7.

The condensation of carboxaldehyde 2 and malonate 3 is conducted in anethereal solvent in the presence of a tertiary amine. Among etherealsolvents there may be mentioned diethyl ether, methyl tert-butyl ether,1,2-dimethyoxyethane, 2-methoxyethyl ether, dioxane, andtetrahydrofuran. Among tertiary amines there may be mentioned pyridines(pyridine, picoline, lutidine, and collidine) and trialkylamines(trimethylamine, triethylamine, and tripropylamine). Tetrahydrofuran andtriethylamine are the preferred solvent and tertiary amine,respectively, While the condensation temperature is not critical, thereaction is preferably performed at about ambient temperature (25° C.),although reduced temperatures (about 0° C. to about 25° C.) or elevatedtemperatures (about 25° C. to the boiling point of the reaction mixture)may be employed.

The alkynylation is performed by treating a halopyridine 4 with analkyne 13 ##STR46## wherein W and n are as above in an acid acceptor,e.g., a di- or trialkylamine, such as, diethylamine, dipropylamine,trimethylamine, triethylamine, or tripropylamine, in the presence ofbis(triphenylphosphine)palladium dichloride/cuprous iodide at atemperature of about 0° to about 75° C. Triethylamine is the preferredacceptor. A temperature of about 50° to 60° C. is the preferredalkynylation temperature. An ethereal solvent may be employed. Etherealsolvents include diethyl ether, methyl tert-butyl ether,1,2-dimethoxyethane, 2-methoxyethyl-ether, dioxane, and tetrahydrofuran.Tetrahydrofuran is the preferred solvent.

The reduction of an alkyl pyridinylpropionate 5 to a propanediol 6 isaccomplished by means of an alkali borohydride in an ethereal solvent ata reduction temperature within the range of about 0° to about 50° C.Included among alkali borohydrides are calcium borohydride, lithiumborohydride, potassium borohydride, and sodium borohydride. Includedamong ethereal solvents are diethyl ether, methyl tert-butyl ether,1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran.A reducing system of lithium borohydride or calcium borohydride intetrahydrofuran at a temperature of from about 0° to 25° C. ispreferred.

The hydrolysis of a carboxamide 6 to an aminodiol 7 may be carried outby conventional hydrolysis techniques. For example, carboxamide 6 may behydrolyzed by an alkali metal hydroxide, i.e., lithium hydroxide, sodiumhydroxide, or potassium hydroxide, in an aqueous alkanol, i.e.,methanol, ethanol, or 1- or 2-propanol, at a hydrolysis temperature ofabout 0° C. to about 100° C.

To prepare a 1-alkylpyridinyl-2-amino-1,3-propanediol 9 wherein W, X,and m are as hereinbeforedescribed, a1-alkynylpyridinyl-2-amido-1,3-propanediol 6 is hydrogenated to a1-alkylpyridinyl-2-amido-1,3-propanediol 8, which is converted to a1-alkylpyridinyl-2-amino-1,3-propanediol 9.

The hydrogenation is effected by treating an alkyne 6 with hydrogen atabout atmospheric pressure to about 60 psi, a pressure of about 40 psibeing preferred, in the presence of a metal catalyst, e.g., platinum,palladium, rhodium, or ruthenium, unsupported or supported on carbon orcalcium carbonate, palladium-on-carbon being preferred, in an alkanol,e.g., methanol, ethanol, or 1- or 2-propanol, ethanol being preferred,at a hydrogenation temperature of about 25° to about 50° C., atemperature of about 25° C. being preferred.

The conversion of pyridinylamidodiol 8 to pyridinylaminodiol 9, i.e.,the hydrazinolysis of 8, is conducted with hydrazine, free or in itshydrated form, in an alkanol such as, for example, methanol, ethanol, or1- or 2-propanol, at a temperature of from about 25° C. to the refluxtemperature of the reaction mixture. Ethanol is the preferred solvent. Ahydrazinolysis temperature of about the reflux temperature of thereaction mixture is also preferred.

Alternatively, entry into the 1-alkynyl- and1-alkylpyridinyl-2-amino-1,3-propanediol systems, i.e., systems offormulas 7 and 9, respectively, wherein W, X, and m are ashereinbeforedescibed may be achieved by alkynylation ofpyridinylcarboxaldehyde 2 wherein W, X, and Y are as above toalkynylpyridinylcarboxaldehyde 10 wherein W, X, and m are as abovefollowed by conversion of pyridinylcarboxaldehyde 10 to alkylpyridinylpropionate 5 wherein R¹¹, R¹², W, X, and m are as above andhydrogenation of an alkynylpyridine 5 wherein R¹¹, R¹², W, X, and m areas above to 11 wherein R¹¹, R¹², W, X, and m are as above. Thealkynylation, conversion, and hydrogenation, i.e., the transformationsof 2 to 5 and 11, via 10, are accomplished by processes substantiallysimilar to the corresponding transformations of 4 to 5, 2 to 4, and 6 to8.

Alkyl 1-alkylpyridinylpropionate 11 wherein R¹¹, R¹², W, X, and m are asabove may be reduced to 1-alkyl pyridinylpropanediol 8 by the processessentially the same as that employed for the reduction of alkylpyridinylpropionate 5 to propanediol 6.

Entry into the 1-alkynylpyridinyl-2-amino-1,3-propanediol series, i.e.,the series encompassing compounds of formulas 5, 6, and 7, is alsoattained by reducing an alkyl pyridinylpropionate 4 wherein R¹¹, R¹², W,X and Y are as hereinbeforedescribed to a pyridinylpropanediol 12 andalkynylating a pyridinyldiol 12, so obtained, to alkynylpyridinyldiol 6.As described above, amidopropanediol 6 is converted to amino propanediol7 by hydrolysis. Similarly, the reduction of 4 to 12 and thealkynylation of 12 to 6 are performed by processes substantially thesame as those utilized for the conversion of 5 to 6 and 4 to 5.

Derivatives of an alkynylpyridinyl-2-amino-1,3-diol 7 are prepared fromamidopropanediol 6 by acylation of 6 wherein R¹², W, X, and m are ashereinbeforedescribed to an amidodiacyloxypropane 15 wherein R¹², R¹³,R¹⁴, W, and m are as hereinbeforedescribed with, for example, analkanoic acid anhydride such as acetic anhydride in the presence oftriethylamine and 4-dimethylaminopyridine to 15, and dioxanylation of 6to amidodioxane 14 wherein R¹², R¹⁵, R¹⁶, W, X, and m are ashereinbeforedescribed with, for example, 2,2-dimethoxypropane in thepresence of para-toluene sulfuric acid. Hydrolysis of 15 as describedfor the conversion of 6 to 7 provides aminopropanediol 7. Anamidodiacyloxypropane 15 is selectively hydrolyzed to an amidodihydroxypropane 20 by, for example, an alkali metal carbonate such as lithium,sodium, or potassium carbonate in an alkanol such as methanol, ethanol,or 2-propanol. Potassium carbonate in methanol is the preferredhydrolysis medium. The hydrolysis proceeds readily at ambienttemperature. Elevated temperatures to the reflux temperature of thehydrolysis medium may be employed.

Acyl derivatives of amidopropanediol 12 wherein R¹², X, and Y are ashereinbeforedescribed are prepared by treating 12 with an alkanoic acidanhydride under the conditions for the conversion of 6 to 15.

To prepare a 1-alkenyl-2-amino-1,3-propanediol 17 wherein W, X, and mare as hereinbeforedescribed a 1-alkynyl-2-amino-1,3-propanediol 6wherein R¹², W, X, and m are as above is hydrogenated to a1-alkenyl-2-amino-1,3-propanediol 16 wherein R¹², W, X, and m are asabove and the configuration of the hydrogen atoms of thecarbon-to-carbon double bond is cis, which is hydrolyzed to 17 whereinW, X, and m are also as above.

To fabricate an N,O,O-tribenzyloxycarbonyl-2-amino-1,3-propane 18wherein R¹⁵ is ##STR47## and 2-amino-1,3-propanediol 9 is treated withN-benzyloxycarbonyloxysuccinimide 20 ##STR48## in the presence of atertiary amine, e.g., triethyl amine in an ethereal solvent, e.g.,tetrahydrofuran at about ambient temperature.

To synthesize a 2-amino-1,3-propanediol 19, a1,3-diacyloxy-2-propanylacetamide 13 is hydrolyzed by hydrazine hydratein the presence of ethanol according to the procedure for the conversionof 8 or 9.

Generally, the ultimate 1-alkylaryl-2-amino-1,3-propanediols of thepresent invention are prepared from 1-alkynylarylcarboxaldehydes. SeeReaction Scheme A for the conversion of 10 to 9 in the pyridine series.In the isoxazole series, the ultimate1-alkylisoxazolyl-2-amino-1,3-propanediols may be prepared, for example,from a 5-(1-alkyl)-3-isoxazolecarboxaldehyde 21 wherein R⁵ is dodecyl.##STR49##

A 3-isoxazolecarboxaldehyde 21 wherein R⁵ is dodecyl, in turn, issynthesized, for example, by condensing 1-nitrotridecane withO-trimethylsilylpropynol in the presence of phenylisocyanate andtriethylamine followed tetrabutylammonium fluoride to affordisoxazolemethanol 22 ##STR50## wherein R⁵ is dodecyl, which is oxidizedby oxalyl chloride:dimethylsulfoxide to 21.

To prepare a 2-alkoxycarbonylamino-1,3-propanediol, for example,1-alkynyl-2-t-butyloxycarbonylamino-1,3-propanediol 6 wherein R¹² isOC(CH₃)₃, a 1-alkynyl-2-amino-1,3-propanediol 7 is acylated withdi-t-butyldicarbonate in the presence of a base such as sodiumbicarbonate in a halocarbon solvent such as chloroform at an elevatedtemperature of about 60° C.

To prepare a 2-dialkylamino-1,3-propanediol, for example, a1-alkenyl-2-dimethylamino-1,3-propanediol 23, a1-alkenyl-2-amino-1,3-propanediol 17 is reductively alkylated withformaldehyde such as formalin in the presence of a reducing agent suchas sodium cyanoborohydride in a solvent such as acetonitrile at ambienttemperature.

Additional N-substituted 2-amino-1,3-propanediols of the presentinvention are prepared by acylation of an aminodiol, for example, athienylaminodiol 30. Thus, treatment of amino 30 with an isocyanate 34

    R.sup.27 N═C═O                                     34

wherein R²⁷ is as hereinbeforedescribed affords a urea 31 wherein R⁵,R²⁷, and X are as hereinbeforedescribed, with an acyl halide 35

    R.sup.6 COHal                                              35

wherein R⁶ is as hereinbeforedescribed affords an amide 32 wherein R⁶ isas hereinbeforedescribed and Hal is chloro or bromo, and withhaloformate 36

    R.sup.28 OCOHal                                            36

wherein R²⁸ and Hal are as hereinbeforedescribed affords a urethane 33.More specifically, treatment of amine 30 with an isocyanate 34 in adipolar aprotic solvent (e.g., dimethylacetamide, dimethylformamide,hexamethylphosphoramide, or dimethylsulfoxide) in the presence of anacid acceptor (e.g., pyridine, 4-dimethylaminopyridine, triethylamine,or tripropylamine), or in a halocarbon (dichloromethane,trichloromethane, or 1,1- or 1,2-dichloroethane) affords urea 31.Similarly, treatment of amine 30 with a carboxylic acid halide 35 or ahaloformate 36 in a dipolar aprotic solvent and acid acceptor such asthose mentioned above provides amide 32 and urethane 33, respectively.While the reaction temperature at which the acylations are preformed arenot narrowly critical, the transformations proceed at a reasonable rateat a temperature between about -10° C. and about ambient temperature. Areaction temperature of about -10° C. or about ambient temperature ispreferred. The preferred dipolar aprotic solvent is dimethylformamide;the preferred halocarbon is dichloromethane.

The conversion of an N-acyl-2-amino-1,3-diol 6 to a5-acylamino-2,2-dialkyl-1,3-dioxane 14 is depicted in Reaction Scheme Band described hereinbefore in the specification. A5-amino-2,2-dialkyl-1,3-dioxane 37 is prepared form 2-amino-1,3-diol 30by employing substantially the same conditions as hereinbeforementioned.A cosolvent such as a halocarbon, i.e., dichloromethane may be utilized.See Reaction Scheme E.

To prepare an oxazolinylmethane 38, a 2-amino-1,3-diol 30 is condensedwith a benzonitrile 39 ##STR51## wherein W is an hereinbeforedescribedin the presence of a base, for example, an alkali metal carbonate suchas lithium, sodium, or potassium carbonate, potassium carbonate beingpreferred, at an elevated temperature within the range of about 80° C.to about 140° C., a condensation temperature of about 110° C. beingpreferred, in a high boiling solvent system consistent with the reactiontemperature chosen to provide a reasonable rate of reaction. Includedamong such solvent systems are mixtures of trihydric alcohols, e.g.,glycerol, and dihydric alcohols, e.g., ethylene glycol, suitable formaintaining a condensation temperature of about 110° C.

To protect the arylic hydroxyl group, i.e., the hydroxyl group at the1-position of the propane chain of all amidic propanoic ester forenvisioned transformations, compound 40, for example, is treated with asilyl halide 43 ##STR52## wherein R²⁹ is alkyl and Hal is chloro orbromo, preferably t-butyldimethylsilyl chloride, in the presence of aacid acceptor such as an imidazole, including imidazole itself, in adipolar aprotic solvent comprising dimethylacetamide, dimethylformamide,hexamethylphosphoramide, or dimethylsulfoxide, dimethylformamide beingpreferred, to provide a silyloxy ester 41. The introduction of theprotecting group proceeds readily at ambient temperature; however,reduced or elevated temperatures within the range of about 10° C. to 40°C. may be employed. Silyloxy ester 41 is then reduced to silyloxycarbinol 42 by processes such as those hereinbeforedescribed to theconversion of 5 to 6.

The transformations depicted in Reaction Schemes A to E refer toconversions in both the erythro- and threo- series. See pages 5 and 6for a discussion of this nomenclature. threo-Compounds are prepared fromthe corresponding erythro-anologs by the conversions shown in ReactionScheme F. Treatment of an erythro-hydroxyamide 43 withtriphenylphosphine and diethyl azodicarboxylate in an ethereal solventsuch as, e.g., tetrahydrofuran, provides, with inversion at the arylicposition, a threo-carbalkoxyoxazoline 44, which is hydrolyzed underacidic conditions, i.e., aqueous acetic acid, at a hydrolysistemperature within the range of about ambient temperature to about 75°C., a reaction temperature of about 50° C. being preferred, to athreo-hydroxyester 45. Reduction of the ester group of an amidic ester45 with, for example, lithium borohydride, as hereinbeforedescribed forthe conversion of 5 to 6, affords a threo-amidic diol, which ishydrolyzed by, for example, aqueous sodium hydroxide to athreo-aminodiol 47.

To fabricate a dialkylaminoalkoxypropanol 49 wherein R¹⁵ is alkyl and Rand X are as hereinbeforedescribed, an aminodiol 30 is N-dialkylated bythe process for the conversion of 17 to 23 to provide a dialkylaminodiol48, which is O-alkylated to provide a dialkylaminoalkoxycarbinol 49. TheO-alkylation is accomplished by treating 48 with an alkali metal hydridesuch as lithium, sodium, or potassium hydride, potassium hydride beingpreferred, in a dipolar aprotic solvent (e.g., dimethylacetamide,dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide) to forman alkoxy anion, which in turn is treated with a dialkyl sulfate 51

    (R.sup.15).sub.2 SO.sub.4                                  51

wherein R¹⁵ is as hereinbeforementioned at ambient temperature to forman alkoxycarbinol 49.

An isoindoledione 50 is prepared by heating an aminodiol 30 with aphthalic anhydride 52 ##STR53## wherein W is as hereinbeforedesribed atan elevated temperature of about 100° C.

Various other N-substituted derivatives of a 2-amino-1,3-propanediol 30are prepared by the processes shown in Reaction Schemes H and I. Thus,alkylation of a oxazolinylmethanol 38 with an alkyl halide 57

    R.sup.15 Hal                                               57

wherein R¹⁵ is as hereinbeforedescribed and Hal is bromo, chloro, oriodo followed by hydrolysis affords an alkylaminopropanediol 56 whereinR¹⁵ is alkyl. The alkylation is performed in a dipolar aprotic solventsuch as, for example, dimethylsulfoxide at about ambient temperature.The hydrolysis is effected without isolation of the alkylation productby means of an aqueous alkali metal hydroxide such as, for example,sodium hydroxide at a temperature within the range of about ambienttemperature to about 100° C., a hydrolysis temperature of about 60° C.being preferred.

In contrast to the abovementioned process, alkylation of 38 with analkyl halide 57 provides a methoxymethyloxazoline 53, which ishydrolyzed first to a methoxybenzamide 54 and then to a methoxyamine 55.The alkylation is carried out by forming the alkoxide ion of 38 of meansof an alkali metal hydride such as sodium hydride in a dipolar aproticsolvent such as dimethylformamide at about ambient temperature toprovide an O-alkoxymethyl oxazoline 53.

The first hydrolysis, i.e., the conversion of an oxazoline 53 to anamide 54 is accomplished under acidic conditions, for example, by anaqueous carboxylic acid such as aqueous acetic acid at a hydrolysistemperature of about 25° to about 75° C. The preferred hydrolysistemperature is about 50° C. The second hydrolysis is effected by anaqueous alkali metal hydroxide such as aqueous sodium hydroxide in analkanol (e.g. methanol, ethanol, 1- or 2-propanol, or1,1-dimethylethanol) at a hydrolysis temperature with in the range ofabout 50° to about 90° C. Ethanol is the preferred solvent. A hydrolysistemperature of about 70° C. is the preferred.

Additional N-substituted derivatives of a 2-aminopropanediol 30 areprepared by the methods outlined in Reaction Scheme I. Thus, acylationof a 1,3-propanediol 33 by the procedure hereinbeforedescribed for theconversion of 6 to 15 gives a 1,3-dialkanoyloxycarbamate 58 which isalkylated and hydrolyzed to a 1,3-dihydroxy N-alkylcarbamate 59. Thealkylation is achieved by the procedure described for the conversion of48 to 49. The hydrolysis of 58 by aqueous potassium carbonate in analkanol (e.g., methanol, ethanol, 1- or 2- propanol, or1,1-dimethylethanol). Methanol is preferred; a hydrolysis temperature ofabout ambient temperature is also preferred.

Similarly, reduction of a dihydroxyamide 60 with an alkali metalaluminum hydride, for example, lithium aluminum hydride in an etherealsolvent, for example, diethyl ether/tetrahydrofuran at about ambienttemperature affords an N-ethyldihydroxyamine 61, which is acylated witha carboxylic acid anhydride 64

    (R.sup.31 CO).sub.2 O                                      64

wherein R³¹ is alkyl in the presence of a base, for example, a mixtureof triethylamine and 4-dimethylaminopyridine in an ethereal solvent, forexample, tetrahydrofuran to provide an O,O-dialkanoyloxyamide 62. Anamide 62 is then hydrolyzed under basic conditions, for example,potassium carbonate in methanol to give a dihydroxy-N-ethylamide 63.

The presence of chiral centers at positions 1 and 2 of the present2-amino-1,3-propanediols, and derivatives thereof, provides anopportunity to prepare stereochemical isomers of the ultimate productsand thereby adduce whether the enantiomers of this series of compoundsexhibit different pharmacological properties, as has been generallydeserved in the art. Significantly, desirable properties generallyreside in an enantiomer, while adverse properties inhere in the other.

To gain access to the enantiomers of the present2-amino-1,2-propanediols, and derivatives thereof, a thiophene 64wherein R is as hereinbeforedescribed is condensed with a chiral1,1-dialkylalkyl-4-formyl-2,2-dialkyl-3-oxazolidinecarboxylate 70##STR54## wherein R³² is alkyl, the preparation of which is described inG. Garner and J. M. Park, Journal of Organic Chemistry, 52, 2761 to 2367(1987), to afford a mixture of diastereomeric hydroxyoxazolidines 65aand 65b, i.e., erythro- and threo- isomers, wherein R³² is as above,which is acylated to a mixture acyloxyoxazolidines 66a and 66b,separated into a pure enantiomer 66b, and hydrolyzed to an enantiomerichydroxyoxazolidine 67, then to an N-acyloxydiol 68, and finally to anenantiomeric 2-amino-1,3-propanediol 69.

The condensation is effected by treating a thiophene 64 with a strongbase, for example, an alkyl- or arylalkali metal such as n-butyllithium,sec-butyllithium or phenyllithium in an ethereal solvent such as1,2-dimethoxyethane, 2-methoxyethylether, dioxane, or tetrahydrofuran,followed by adding, in this case, chiral oxazolidine 70, also in anethereal solvent to the salt so formed to a afford a mixture of theerythro- and threo-hydroxyoxazolidines 65a and 65b. The condensation isgenerally carried out at a reduced temperature in the range of about-100° to -50° C., a reaction temperature of about -78° C. beingpreferred.

The acylation is readily achieved by processes hereinbeforedescribed forthe conversion of 6 to 15, namely, by treating a mixture of 65a and 65bwith a carboxylic acid anhydride 71

    (R.sup.32 CO).sub.2 O                                      72

wherein R³² is alkyl in an ethereal solvent (e.g., tetrahydrofuran) inthe presence of a base or combination of bases (e.g., triethylamineand/or 4-dimethylaminopyridine) at room temperature to yield a mixtureof O-acyloxyoxazolidines 66a and 66b.

The separation of the diastereomeric mixture is accomplished byselective crystallization techniques or chromatographic methods, forexample, thin-layer, column, including high pressure and flashchromatography, using suitable absorbents and eluents. Among absorbents,there may be mentioned silica gel, cellulose, magnesium silicate,activated aluminum oxide and resins (e.g., Amberlite and Dowex ionexchange resins). Among suitable chromatography solvents, these may bementioned acetone, dichloromethane, ethyl acetate, 2-ethoxyethyl ether,ethanol, hexanes, and heptane. Particularly suitable absorbent andsolvent for the separation of the diastereomeric acylates are silica geland ethyl acetate/heptane in a flash chromatographic apparatus.

The hydrolysis of an enantiomer 66b to a hydroxyoxazolidine 67 isachieved by means of an alkali metal carbonate (e.g. lithium, potassium,or sodium carbonate) in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or 1,1-dimethylethanol) at about ambient temperature; reducedtemperatures in the range of about 0° C. to about ambient temperatureand elevated temperatures in the range of about ambient temperature toabout 50° C. may be employed to effect the hydrolysis.

The hydrolysis of a hydroxyoxazolidine 67 to an N-acyloxydiol 68 ispreformed in an alkanol (e.g., methanol, ethanol, 1- or 2-propanol, or1,1-dimethylethanol) in the presence of an organic acid (e.g., sulfonicacids, such as methanesulfonic acid, benzenesulfonic acid, or4-methylbenzenesulfonic acid, or a carboxylic acid, such astrifluoroacetic acid). Sulfonic acids are preferred;4-methylbenzenesulfonic acid is most preferred. Methanol is alsopreferred. The hydrolysis of occurs readily at ambient temperature.Reduced temperatures in the range of about 0° C. to ambient temperatureand elevated temperatures in the range of about ambient temperature toabout 50° C. may be employed, however.

The hydrolysis of an N-acyloxydiol 68 to a 2-aminopropan-1,3-diol 69 isachieved by means of a mineral acid in an alkanol, or mixtures thereof.Included among mineral acids are hydrochloric, hydrobromic, andhydroiodic acids. Hydrochloric acid is preferred. Included amongalkanols are methanol, ethanol, 1- and 2-propanol, and1,1-dimethylethanol. Mixtures of methanol and ethanol are preferred.While the hydrolysis temperature is not narrowly critical, it isconvenient to carry out the hydrolysis at ambient temperature.

The enantiomers of the 2-amino-1,2-propanediols of the presentinvention, and derivatives thereof, are also prepared by condensing acarboxaldehyde 72 with, for example, a chiralhaloacetyl-4-phenylmethyloxazolidinone 77a ##STR55## wherein Hal ischloro, bromo, or iodo, and W is as hereinbeforedescribed, having theS-configuration at the 4-position, the preparation of which is describedin D. A. Evans and A. E. Weber, Journal of the American ChemicalSociety, 109, 7151 (1981), to provide an oxazolidinylhalohydrin 73,which is converted to an azidohydroxyoxazolidine 74, cleaved to anazidohydroxypropionate 75, and reduced to an aminodiol 76. Thecondensation is effected by treating an aldehyde 72 with ahaloacetyloxazolidinone 73 in the presence of a condensing agent, forexample, a dialkyl borontriflate 78

    CF.sub.3 SO.sub.3 B(R.sup.34).sub.2                        78

wherein R³⁴ is alkyl, such as di-n-butyl borontriflate and an acidacceptor, for example, a trialkylamine such as triethylamine or4-dimethylaminopyridine, triethylamine being preferred, in etherealsolvent. Among ethereal solvents, there may be mentioned diethyl ether,1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane, and tetrahydrofuran.Diethyl is preferred. The condensation is generally carried out at areduced temperature within the range of about -25° to about 100° C., acondensation temperature of about -78° C. being preferred.

The conversion of a halohydrin 73 to an azidohydrin 74 is accomplishedby treating a halo derivative 73 with an alkali metal azide, e.g.,lithium, sodium or potassium azide, sodium azide being preferred, in adipolar aprotic solvent, e.g., dimethylacetamide, dimethylformamide,hexamethylphosphoramide, N-methylpyrrolidione, or dimethylsulfoxide,dimethylsulfoxide being preferred, at about ambient temperature,although reduced temperatures (about 0° C. to about ambient temperature)or elevated temperatures (about ambient temperature to about 50° C.) maybe employed.

The cleavage of a 4(S)-phenylmethyloxazolidinone 74 to an ester 75 isachieved by treating an oxazolidinone 74 with an alkoxymagnesium halide,for example, methoxymagnesium bromide, prepared in situ from analkylmagnesium halide, for example, methylmagnesium bromine, and analkanol, for example, methanol in an alkanol/halocarbon solvent, forexample methanol/dichloromethane at about 0° C. Elevated temperatures upto about 50° C. may be employed to effect the cleavage.

The reduction of an azidoester 75 to an enantiomeric2-amino-1,3-propanediol 76 having the S-absolute configuration isrealized by treating an azidoester 75 with an alkali metal hydride, forexample, lithium aluminum hydride (although sodium or potassium aluminahydride may be used), in diethyl ether (although other ethereal solventssuch as 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran ordioxane may also be used). The reduction of both the azido and estergroups proceeds smoothly at about 0° C. Elevated temperatures dependentupon the boiling point of the solvent system may also be employed. A2-aminopropane-1,3-diol 82, having the R- absolute configuration, isprepared by the aforementioned processes starting from carboxaldehyde 72and haloacetyl-4-phenylmethyloxazolidinone 77b ##STR56## wherein Hal isas hereinbeforementioned and W is as hereinbeforedescried, having theR-configuration at the 4-position.

Alternatively, an enantiomeric 2-aminopropane-1,3-diol of the presentinvention is prepared by reducing a trans-propenoate 83, prepared froman appropriate aldehyde and a (carbalkoxymethylene)triphenylphosphoranein a conventional Wittig reaction, is reduced to a carbinol 84 andepoxidized under asymmetric conditions to an epoxycarbinol 85, which inturn, is condensed with a benzoylisocyanate to provide abenzoylcarbamate, 86 cyclized to an oxazolidinone 87, and cleaved to anaminopropanediol 88.

The reduction is achieved by treating an alkyl propenoate 83 with analuminum hydride such as, for example, diisobutylaluminium hydride in anethereal solvent such as, for example, tetrahydrofuran, at a reducedtemperature of about -78° C. to provide a carbinol 84.

The asymmetrically induced expoxidation of a trans-alkyl propenate 84 toa 2S-trans-oxirane 85 is accomplished by means of a reaction systemcontaining a base, an epoxidizing agent, and a chiral reagent in asuitable solvent. Among bases, there may be mentioned alkoxides such asalkali metal alkoxides, alkaline earth alkoxides, and transition metalalkoxides. Examples of alkali metal alkoxides include lithium, sodium,and potassium alkoxides. Examples of alkaline earth alkoxides includemagnesium and calcium alkoxides. Examples of transition alkoxidesinclude titanium, nickel, zinc alkoxides. Examples of alkoxy groupsinclude methoxide, ethoxide, 1- and 2-propoxide, and2,2-dimethylethoxide. Transition metal alkoxides are preferred; titanium(IV) 2-propoxide is most preferred.

A variety of epoxidizing agents may be used in this enantioselectivesynthesis. Among these are organic peracids, for example, perbenzoicacid, peracetic acid, performic acid, and monoperththalic acid, hydrogenperoxide and alkylhydroperoxides derivatives thereof such astert-butylhydroxyperoxide, the preferred reagent.

The key reagent in this heterogeneous asymmetric epoxidation, the chiralreagent, may be selected from a wide group of optically active organicacids and ester or amide derivatives thereof. Included within this groupare tartaric acid and dialkyltartrates, and camphoric acid and dialkylcamphorates. Optically active dialkyltartrates are preferred;di-2-propyltartrate is most preferred. When (+)-di-2-propyltartrate isused, a 2S-trans-oxirane 85 is formed selectively.

Suitable solvents for the expoxidation include halocarbons such as forexample dichloromethane, 1,1- and 1,2-dichloroethane and ethylenedichloride. Dichloromethane is preferred.

The epoxidation is generally conducted at a reduced temperature of about-78° to about 0° C., a reaction temperature of about -20° C. beingpreferred.

The condensation of an optically active hydroxyoxirane 85 with abenzoylisocyanote 89 ##STR57## wherein W is as hereinbeforedefined isconveniently carried out in a halocarbon solvent of the type mentionedimmediately above, generally in dichloromethane at about ambienttemperature, which temperature is not narrowly critical.

The cyclization of a carbamate 86 to a hydroxyoxazolidinone 87 iseffected by an alkali metal hydride selected from the group comprisinglithium, sodium, or potassium hydride in a ethereal solvent selectedfrom the group comprising diethyl ether, 2-methoxyethyl ether,1,2-dimethoxyether, tetrahydrofuran, or dioxane. Sodium hydridesuspended in tetrahydrofuran is preferred, as is a cyclizationtemperature of about the reflux temperature of the reaction medium,although the reaction proceeds readily at reduced temperatures to aboutambient temperature.

The hydrolysis of hydroxyoxazolidinone 87 to aminopropanediol 88 isachieved in an alkanol solvent, e.g., methanol, ethanol, 1-, 2-propanolor 2,2-dimethylethanol, by means of a base such as aqueous alkali metalhydroxide, e.g., sodium or potassium hydroxide, about ambienttemperature. Ethanol and aqueous sodium hydroxide are the preferredsolvent and base.

By applying the aforedescribed process depicted in Reaction Scheme M andemploying the antipode of the chiral reagent, e.g., (-)-diethyltartratein the preferred synthesis, 2-amino-1,3-propanediol 93 is obtained viahydroxy oxirane 90, benzoylcarbamate 91, hydroxyoxazolidinone 92.

A 1-alkenyl-2-amino-1,3-propanediol, e.g., a1-alkenylpyridinyl-2-amino-1,3-propanediol 17, is prepared by reductionof a 1-alkynylpyridinyl-2-acylamino-1,3-propanediol 6 via a1-alkenylpyridinyl-2-acylamino-1,3-propanediol 16. See Reaction SchemeC. Alternatively, a 1-alkenyl-2-amino-1,3-propanediol, e.g., a1-alkenylthienyl-2-amino-1,3-propanediol 27, is prepared by condensationof a halothiophenecarboxyaldehyde 25 wherein X is bromo with atri-n-butyl-1-alkenylstannane 24 in the presence of2,6-di-t-butyl-4-methylphenol andtetrakis(triphenylphosphine)palladium(O) in an aromatic solvent such astoluene at room temperature to a 1-alkenylthiophenecarboxaldehyde 26(see Reaction Scheme D), which, in turn, is converted to a2-amino-1,3-diol 27 and derivatives thereof by the processes outlined inReaction Schemes A, B, and C.

The requisite tri-n-butyl-1-alkenylstannane 24 is prepared by reductivecondensation of an alkyne 28 with tri-t-butylhydride in the presence ofazobisisobutyronitrile.

To synthesize a 2-amino-1-propanol 98 of the present invention, analdehyde 94 is reduced to a methanol 95 wherein R³⁸ is hydrogen byconventional methods, which is convened to an amidomalonate 96 whereinR⁵ and X are as hereinbeforedescribed and R³⁷ is alkyl via a sulfonate95 wherein R³⁸ is SO₂ R³⁹ wherein R³⁹ is alkyl and, in turn, reduced toa hydroxyamide 97 and hydrolyzed to an aminocarbinol 98. The conversionis carried out by treating a methanol 95 (R³⁸ is hydrogen) with analkylsulfonyl halide 99a

    R.sup.39 SO.sub.2 Hal                                      99a

wherein R³⁹ is alkyl and Hal is chloro or bromo in a halocarbon solvent,e.g., dichloromethane, trichloromethane, 1,1- and 1,2-dichloroethane,dichloromethane being preferred, in the presence of an acid acceptor,e.g., a tertiary amine such as triethylamine, pyridine, and4-dimethylpyridine, triethylamine being preferred, at about ambienttemperature to provide a sulfonate 95 (R³⁸ is SO₂ R³⁹). Optionally,without isolation, the sulfonate 95 is then treated with anamidomalonate 100 ##STR58## wherein R³⁸ is alkyl in an alkanol in thepresence of a corresponding alkali metal alkoxide. Included amongalkanols and corresponding alkali metal alkoxides are methanol andlithium, sodium, and potassium methoxide, ethanol and lithium, sodium,and potassium ethoxide, 1- and 2- propanol and lithium, sodium, andpotassium 1- and 2-propoxide, and 1,1-dimethyl ethanol and lithium,sodium, and potassium 1,1-dimethylethoxide. Sodium ethoxide in ethanolis preferred. This step of the conversion proceeds readily at aboutambient temperature.

The reduction of a malonate 96 to an amido alcohol 97 is performed bytreating the former with an alkali metal borohydride such as, forexample, sodium or lithium borohydride, lithium borohydride beingpreferred, in an ethereal solvent such as, for example, diethylether,2-methoxyethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, and dioxane,tetrahydrofuran being preferred, at a reduction temperature within arange compatible with the reaction medium. When tetrahydrofuran is usedas the solvent, a reaction temperature within the range of about 40° toabout 80° C. is preferred, a reaction temperature of about 60° C. ismost preferred.

The hydrolysis of an amide 97 to an amino alcohol 98 is achieved bytreating an amide 97 with an alkali metal hydroxide, for example,lithium, sodium, or potassium hydroxide, sodium hydroxide beingpreferred in alkanol, for example, methanol, ethanol, 1- or 2-propanol,or 1,1-dimethylethanol, ethanol being preferred, at a hydrolysistemperature of about 65° C., when ethanol is used as the solvent.

To gain entry into the indole series, i.e., to prepare a2-amino-1,3-propanediol 104 characterized by the presence of an indolemoiety, the nitrogen of an indole carboxaldehyde 101 is protected by,for example, a sulfonyl function to provide a protectedindolecarboxaldehyde 102, which may be converted to anindolyaminopropanediol 104 by the processes described herein andconventional methods. To protect the indole function prior to subsequenttransformations, an indole carboxaldehyde 101 wherein X is bromo istreated with a sulfonyl halide 99b ##STR59## wherein W is ahereinbeforedescribed and Hal is bromo or chloro in an ethereal solvent,for example, tetrahydrofuran in the presence of an acid acceptor, forexample, triethylamine at a reaction temperature about 65° C. Otherethereal solvents and acid acceptors may be employed, however. Amongthem may be mentioned dioxane, 1,2-dimethoxyethane and 2-methoxyethylether, and pyridine and 2-dimethylaminopyridine, respectively. Otherreaction temperatures, among them temperatures in the range of about 50°to 80° C., may also be employed.

To fabricate a 2-amino-1,3-propanediol having an alkanoylarylsubstituent at the 3-position of the aminodiole side-chain, i.e., toprepare, for example, an alkanoylphenylaminopropanediol 106 whereinR^(5') is alkyl, alkynylphenylaminopropanediol is hydrolyzed in anethereal solvent, for example, tetrahydrofuran in the presence ofmercuric oxide and a mineral acid, for example, sulfuric acid at apreferred reaction temperature of about room temperature.

To construct a 2-aminopropane-1,3-diol having an alkoxyaryl moiety atthe 3-position of the aminodiol side-chain, i.e., to prepare, forexample, alkoxy phenylaminopropanediol 111 wherein R⁵ is ashereinbeforedescribed, an alkanoyloxy benzaldehyde 107 wherein R⁴¹ isalkyl is converted to an amidoester 108 wherein R¹¹, R¹², and R⁴¹ are ashereinbeforedescribed by processes also hereinbeforedescribed, which isreduced to hydroxyphenyldiol 109 wherein R¹² is as hereinbeforedescribedand, in turn, alkylated to alkoxyphenyldiol 110 and hydrolyzed byprocesses hereinbeforedescribed to alkoxyphenylaminopropanediol 111. Thereduction of an alkanoylphenylpropionate 108 is achieved by treating apropionate 108 with a alkali metal borohydride, e.g., lithiumborohydride, in ethereal solvent, for example, tetrahydrofuran at areduced temperature of about 0° C. The alkylation is performed bytreating a phenol 109 with an alkyl halide 112

    R.sup.5 Hal                                                112

wherein R⁵ is as hereinbeforedescribed and Hal is bromo, chloro, or iodoin a dipolar aprotic solvent, e.g., dimethylacetamide,dimethylformamide, hexamethylphosphoramide, or dimethylsulfoxide,dimethylformamide being preferred, in the presence of an alkali metalcarbonate, including lithium, sodium, potassium, and cesium carbonate,and cesium carbonate being preferred. The alkylation is preferablycarried out at about room temperature. Reduced temperatures within therange of about 0° C. to about room temperature and elevated temperaturesform about room temperature to about 100° C. may be employed to effectthe alkylation.

By employing the appropriate starting materials and the processesdescribed herein, additional 2-amino-1,3-propanediols of the presentinvention may be fabricated. For instance, starting from availablesubstituted naphthalenes, naphthylaminopropanediols 112 ##STR60##wherein R⁵ and X are as hereinbeforedescribed may be constructed.

The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols ofthe present invention are useful as agents for the relief of memorydysfunction, particularly dysfunctions associated with decreasedcholinergic activity such as those found in Alzheimer's disease. Reliefof memory dysfunction activity of the instant compounds is demonstratedin the dark avoidance assay, an assay for the determination of thereversal of the effects of scopolamine induced memory deficitsassociated with decreased levels of acetylcholine in the brain. In thisassay, three groups of 15 male CFW mice were used--a vehicle/vehiclecontrol group, a scopolamine/vehicle group, and a scopolamine/druggroup. Thirty minutes prior to training, the vehicle/vehicle controlgroup received normal saline subcutaneously, and the scopolamine/vehicleand scopolamine/drug groups received scopolamine subcutaneously (3.0mg/kg, administered as scopolamine hydrobromide). Five minutes prior totraining, the vehicle/vehicle control and scopolamine/vehicle groupsreceived distilled water and the scopolamine/drug group received thetest compound in distilled water.

The training/testing apparatus consisted of a plexiglass boxapproximately 48 cm long, 30 cm high and tapering from 26 cm wide at thetop to 3 cm wide at the bottom. The interior of the box was dividedequally by a vertical barrier into a light compartment (illuminated by a25-watt reflector lamp suspended 30 cm from the floor) and a darkcompartment (covered). There was a hole at the bottom of the barrier 2.5cm wide and 6 cm tall and a trap door which could be dropped to preventan animal from passing between the two compartments. A CoulbournInstruments small animal shocker was attached to two metal plates whichran the entire length of the apparatus, and a photocell was placed inthe dark compartment 7.5 cm from the vertical barrier and 2 cm off thefloor. The behavioral session was controlled by PDP 11/34 minicomputer.

At the end of the pretreatment interval, an animal was placed in thelight chamber directly under the light fixture, facing away from thedoor to the dark chamber. The apparatus was then covered and the systemactivated. If the mouse passed through the barrier to the darkcompartment and broke the photocell beam within 180 seconds, the trapdoor dropped to block escape to the light compartment and an electricshock was administered at an intensity of 0.4 milliamps for threeseconds. The animal was then immediately removed from the darkcompartment and placed in its home cage. If the animal failed to breakthe photocell beam within 180 seconds, it was discarded. The latency isseconds for each mouse was recorded.

Twenty-four hours later, the animals were again tested in the sameapparatus except that no injections were made and the mice did notreceive a shock. The test day latency in seconds for each animal wasrecorded and the animals were then discarded.

The high degree of variability (due to season of the year, housingconditions, and handling) found in one trial passive avoidance paradigmis well known. To control for this fact, individual cutoff (CO) valueswere determined for each test, compensating for interest variability.Additionally, it was found that 5 to 7% of the mice in thescopolamine/vehicle control groups were insensitive to scopolamine at 3mg/kg, sc. Thus, the CO value was defined as the second highest latencytime in the control group to more accurately reflect the 1/15 expectedcontrol responders in each test group. Experiments with a variety ofstandards repeated under a number of environmental conditions led to thedevelopment of the following empirical criteria: for a valid test, theCO value had to be less than 120 sec and the vehicle/vehicle controlgroup had to have at least 5/15 animals with latencies greater than CO.For a compound to be considered active the scopolamine/compound grouphad to have at least 3/15 mice with latencies greater than CO.

The results of the dark avoidance test are expressed as the number ofanimals per group (%) in which this scopolamine induced memory deficitis blocked as measured by an increase in the latency period. Relief ofmemory dysfunction activity for representative compounds of the presentinvention is presented in Table 1.

                  TABLE 1    ______________________________________                              Percent of Animals                              with Scopolamine                    Dose      Induced Memory    Compound        (mg/kg, sc)                              Deficit Reversal    ______________________________________    ethyl erythro-2-acetamido-                    3.0       27    3-[6-(1-decynyl)-2-pyridinyl]-    3-hydroxypropionate    erythro-N-{1-[6-(1-decynyl)-                    3.0       33    2-pyridinyl]-1,3-dihydroxy-    2-propanyl}acetamide    physostigmine   0.31      20    ______________________________________

Scopolamine induced memory deficit reversal is achieved when the present1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediol, andrelated compounds are administered to a subject requiring such treatmentas an effective oral, parenteral or intravenous dose of from 0.01 to 100mg/kg of body weight per day. A particularly effective amount is about25 mg/kg of body weight per day. It is to be understood, however, thatfor any particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols ofthe present invention are also useful as antiinflammatory agents due totheir ability to reduce inflammation in mammals. The antiinflammatoryactivity is demonstrated in the TPA-induced ear edema assay and thearachidonic acid-induced ear edema test (see J. M. Young, et al.,Journal Investigative Dermatology, 80, 48 (1983)).

In the TPA-induced ear edema assay, TPA(12-O-tetradecanoylphorbol-13-acetate) was dissolved in 30/70 propyleneglycol/ethanol and was applied to the right ear of groups of 6 femaleSwiss Webster mice, which were housed together in a cage under standardconditions for 1 week prior to use with food and water ad lib, at avolume of 20 μl so that a total of 10 μg of TPA is delivered to theinner and outer surfaces of the ear. The test compound was dissolved inthe vehicle and was applied to the right ear (the inner and outersurface) at a volume of 20 μl so that a total of 10 μg of the compoundwas delivered to the ear. After about 5 hours, the animals weresacrificed, a 4 mm diameter plug was taken from each ear and weighed.The difference between the right and left ear plug weights for eachanimal was determined. The antiinflammatory activity of the testcompound is expressed as the mean percent change in the ear plug weightof the treated animals compared to the mean percent change in the plugweight of the control animals. Antiinflammatory activity ofrepresentative compounds of the instant invention as determined in thisassay are presented below in Table 2.

                  TABLE 2    ______________________________________                      Antiinflammatory Activity                      Percent Decrease in Ear Plug    Compound          Weight at 10 μg/ear    ______________________________________    erythro-2-amino-1-                      66    (6-decyl-2-pyridinyl)-    1,3-dihydroxypropane    ethyl erythro-2-acetamido-3-                      50    [6-(1-dodecynyl)-    2-pyridinyl]-3-hydroxypropionate    erythro-N-{1-[6-(1-dodecynyl)-                      59    2-pyridinyl]-1,3-dihydroxy-    2-propanyl}acetamide    erythro-2-amino-1-(6-dodecyl-                      24    2-pyridinyl)-1,3-propanediol    threo-2-amino-1-(6-decyl)-                      30    2-pyridinyl)-1,3-propanediol    D-erythro-sphingosine                      46    ______________________________________

In the arachidonic acid-induced ear edema assay, the test compound wasdissolved in 30/70 propylene glycol/ethanol and was applied to both earsof groups of 6 female Swiss Webster mice, which were housed together ina cage under standard conditions for 1 week prior to use with food andwater ad lib, at a volume of 20 μl so that a total of 1.0 mg of testcompound was delivered to each ear over the inner and outer surfaces.The same volume (20 μl) of vehicle was applied to each ear of a controlgroup of mice. After 30 minutes, arachidonic acid was applied to theright ear of each mouse of each group in the amount of 4 mg/ear. Vehiclewas applied to the left ear of each mouse of each group at a volume of20 μl/ear. After an additional hour, the mice were sacrificed and a 4 mmplug was taken from each ear and weighed. The difference between theright and left ear plugs was determined for each animal. Theantiinflammatory activity of the test compound is expressed as the meanpercent change in the ear plug weight of the treated animals relative tothe mean percent change in weights of control animals' ear.Antiinflammatory activity of representative compounds of the presentinvention as determined in this assay are presented below in Table 3.

                  TABLE 3    ______________________________________                   Antiinflammatory Activity                   Percent Decrease in Ear Plug    Compound       Weight at 1 mg/ear    ______________________________________    erythro-2-amino-1-                    32    (6-decyl-2-pyridinyl)-    1,3-dihyrdroxypropane    D-erythro-sphingosine                   +9    ______________________________________

Inflammation reduction is achieved when the present 1-alkyl-,1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols are administeredtopically, including ophthalmic administration, to a subject requiringsuch treatment as an effective topical dose of from 0.001 to100 mg/kg ofbody weight per day. A particularly effective amount is about 25 mg/kgof body weight per day. It is to be understood however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The 1-alkyl-, 1-alkenyl-, and 1-alkynyl-2-amino-1,3-propanediols of thepresent invention are also useful as inhibitors of tumor or neoplasticcell growth by virtue of their ability to reduce cell proliferation asdemonstrated in the protein kinase C assay. (see U. Kikkawa, et al.,Biochemical and Biophysical Research Communications, 135, 636 (1986) andR. M. Bell, et al. "Methods in Enzymology, Hormone Action," Part J, P.M. Conn, Ed., Academic Press, Inc., New York, N.Y. 1986, page 353).

Protein kinase C enzyme extract was prepared from the brain of maleWistar rats weighing 180 to 200 g and purified by the method of U.Kikkawa, et al., ibid. 636. The purified extract was stored at -80° C.,and aliquots were used in the protein kinase C assay performed by amodification of the method of R. M. Bell, et al., ibid. al 354.

To perform the assay, duplicate aliquots of duplicate samples areemployed. Basal or unstimulated protein kinase C,phosphatidylserine/diacylglycerol stimulated protein kinase C, and testsamples are run in each assay. Protein kinase C extract (1-5 μg ofprotein; 10 μl); an 8 μl solution ofN-2-hydroxyethylpiperazine-N'-2-ethylsulfonic acid (500 mM), magnesiumchloride (40 mM), and ethylenediaminoetetraacetic acid (10 mM);dithiothreitol (20 mM; 8 μl), Type III histone (12 μg; 8 μl), andcalcium chloride (11 mM; 8 μl) was added to each unstimulated proteinkinase C sample assay tube, chilled in ice.Phosphatidylserine/diacylglycerol (4 μg; 8 μl) was added to eachstimulated protein kinase sample assay tube, chilled in ice. The testcompound (10⁻⁴ to 10⁻¹² M in 4 μl dimethylsulfoxide) was added to thetest sample tubes, chilled in ice. The volume for all sample tubes wasbrought to 72 μl with distilled water (18 μl for stimulated samples; 26μl for unstimulated samples without 8 μl ofphosphatidylserine/diacylglycerol). The assay tubes were allowed to warmto 25° C. and an 8 μl mixture of adenosine 5'-triphosphate (100 μM) and³² P-adenosine triphosphate (1 to 2×10⁵ counts per minute) was added toeach tube for a final volume of 80 μl per tube. After 2 min, thereaction (the incorporation of phosphorous into Type III histone) wasterminated by spotting the assay mixture on phosphocellulose paper. Thespots are cut out of the paper and the radioactivity (counts per min) ofeach spot was determined in a scintillation counter. Percent proteinkinase C inhibitory activity, i.e., the percent inhibition of theincorporation of ³² phosphorous from ³² P-adenosine triphosphate intoType III histone, is calculated as follows: ##EQU1##

Protein kinase C inhibitory activity of representative compounds of thepresent invention expressed as the calculated concentration of testcompound effecting a 50% inhibition of phosphorous uptake (IC₅₀) ispresented below in Table 4.

                  TABLE 4    ______________________________________                         Protein Kinase                         Inhibitory Activity    Compound             IC.sub.50 (μM)    ______________________________________    ethyl erythro-2-acetamido-                         29    3-[6-1-dodecynyl)-2-    pyridinyl]-3-hydroxypropionate    cis-erythro-N-{1-[6-(1-dodecenyl)-                         66% @ 100 μM    2-pyridinyl]-1,3-dihydroxy-2-    propanyl}-acetamide    erythro-2-amino-1-(6-dodecyl-2-                         8.5    pyridinyl)-1,3-propanediol    erythro-2-amino-1-(6-decyl-2-                         48    pyridinyl)-1,3-dihydroxypropane    threo-2-amino-1-(6-decyl-2-                         25    pyridinyl)-1,3-dihyrdroxypropane    D-erythro-sphingosine                         6.7    ______________________________________

Protein kinase C inhibition is achieved when the present 1-alkyl-,1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, and relatedcompounds are administered to a subject requiring such treatment as aneffective oral, parenteral, intravenous, or topical dose of from 0.001or 0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 25 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.

The 1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols ofthe present invention are also useful as antibacterial and antifungalagents due to their ability to inhibit bacterial and fungal growth inmammals. Antibacterial and antifungal activity are demonstrated inconventional antimicrobial assays assays (see D. J. Bibel, et al., TheJournal of Investigative Dermatology, 92, 632 (1989).

In the aerobic antibacterial assay, the sensitivity of aerobic bacteriawas tested by means of the agar dilution test in Mueller-Hinton agar.Plates were inoculated with a multipoint inoculator which delivered5×10⁴ CFU/spot of stationary, freshing diluted cultures of the strainsconcerned. The minimun inhibitory concentration (MIC) was taken as thelowest concentration at which no visible growth could be detected after24 hours at 37° C.

In the anerobic assay, the susceptibility of obligate gram-positive andgram-negative anaerobes was tested using the agar dilution test onWilkins-Chalgren agar. Overnight cultures of the appropriate teststrains diluted 1:10 in fresh thioglycollate medium were used as theinoculum. The MICs of the antibiotics were determined after the plateshad been incubated in anaerobic jars for 48 hours at 37° C.

Antibacterial activity or representative compounds of the instantinvention as determined in this assay is presented below in Tables 5 and6.

                  TABLE 5    ______________________________________    Antibacterial activity (MIC, mg/l)                  erythro-2-amino-                  1-(6-decyl-2-pyridinyl)-                                  D-erythro-    Aerobic Bacteria Strain                  1,3-dihydroxypropane                                  sphingosine    ______________________________________    Staph. aureus              SG511   12.50           25.0              285     12.50           25.0              503     6.25            25.0    Strept. pyogenes              308 A   6.25            12.5              77 A    6.25            25.0    Strept. faecium              D       12.50           25.0    E. coli   O 78    12.50           >100.0              TEM     25.00           >100.0              1507E   12.50           >100.0              DC0     12.50           >100.0              DC2     6.25            25.0    S. typhimurium    12.50           >100.0    Klebsiella spp.              1082E   12.50           25.0              1522E   12.50           >100.0    E. cloacae              P99     12.50           >100.0              1321E   12.50           50.0    ______________________________________

                                      TABLE 6    __________________________________________________________________________    Antibacterial activity (MIC, mg/l)    __________________________________________________________________________                  Erythro-2-amino                              Erythro-N-{1-[6-(1-dodecynyl)-                  1-(6-decyl-2-pyridinyl)-                              2-pyridinyl]-1,3-dihydroxy-    Anerobic Bacteria Strain                  1,3-dihydroxypropane                              2-propanyl}acetamide    __________________________________________________________________________    Bact. fragilis               312                  12.50       3.13               960                  6.25        3.13              1313                  12.50       6.25              17390                  12.50       6.25              18125                  12.50       3.13              19016                  12.50       6.25    Bact. ovatus               103                  6.25        3.13    Bact. vulgatus              1446                  12.50       3.13    Bact. thetaiotaom               123                  6.26        3.13              1428                  12.50       6.25              1445                  12.50       6.25    Bact. distasonis              1366                  12.50       6.25    Fusobact. varium              5262                  12.50       6.25              3085                  12.50       6.25    Spaeroph. freundii              1369                  12.50       3.13    Peptostr. anaerobius               932                  12.50       6.25    Propionibact. acnes              6919                  12.50       6.25              6922                  12.50       6.25    Clost. tetani              19406                  12.50       12.50    Clost. perfringens               194                  12.50       12.00    __________________________________________________________________________                  Erythro-2-amino-                  1-[5-(1-dodecynyl)-                                   D-erythro-    Anerobic Bacteria Strain                  2-thienyl]-1,3-propanediol                                   sphingosine    __________________________________________________________________________    Bact. fragilis               312                  6.25             25.0               960                  6.25             12.5              1313                  6.25             25.0              17390                  3.13             25.0              18125                  3.13             25.0              19016                  6.25             25.0    Bact. ovatus               103                  3.13             12.5    Bact. vulgatus              1446                  3.13             25.0    Bact. thetaiotaom               123                  3.13             25.0              1428                  6.25             25.0              1445                  3.13             25.0    Bact. distasonis              1366                  3.13             12.5    Fusobact. varium              5262                  3.13             25.0              3085                  6.25             25.0    Spaeroph. freundii              1369                  1.56    Peptostr. anaerobius               932                  6.25             12.5    Propionibact. acnes              6919                  3.13             12.5              6922                  1.56             12.5    Clost. tetani              19406                  6.25             50.0    Clost. perfringens               194                  6.25             6.25    __________________________________________________________________________

In the antifungal assay, utilizing a microtitration technique (U-shaped,96 well-plate), the test compound (10 mg) is dissolved in a suitablesolvent (10 ml dist. water, or 1 ml org. solvent+9 ml dist. water).

The microtiter plate is prepared as follows: The wells are each filled(2 rows/strain) with 50 μl neopeptone-dextrose broth (12-channelpipette). In addition, one row/strain is coated with 50 μlyeast-nitrogen base/well for yeasts and moulds. Subsequently, 50 μlcompound solution are added to each well in the first row, mixed anddiluted further by transferral of 50 μl respectively in the ratio 1:2.All wells are then inoculated with 150 μl standardized organismsuspension (yeasts: 1×10³ organisms/ml suspension; cutaneous fungi andmoulds: 1.6×10⁵ organisms/ml suspension); the total volume is 200 μl perwell.

There is also a growth control (inoculated, not medicated), a solventcontrol (inoculated, not medicated, containing solvent as in medicatedrows) and a negative control (not inoculated, not medicated).

Incubation for 5 days at 30° C. is followed by photometric evaluation.The obtained measurements are checked visually (macroscopically andmicroscopically) and corrected where necessary.

Criteria for Evaluation of the Antimycotic Effect

a. Photometric measurements (matrix method)

b. Growth, macroscopic evaluation

c. Growth, microscopic evaluation (inversion light microscope, magn.64×).

Antifungal activity of representative compounds of the instant inventionas determined in the microtiter assay is presented below in Table 7.

                  TABLE 7    ______________________________________                              Antifungal Activity    Pathogen         Strain   MIC [μg/ml]    ______________________________________    erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-    2-propanyl}acetamide    Trichophyton Mentagrophytes                     100/25   7.810    Trichophyton Rubrum                     101/85   31.250    Microsporum Canis                     150/353  0.970    Candida Albicans 200/175  125.000    Aspergillus Niger                     500/284  125.000    Trichophyton Vaginalis                     111/216  15.625    erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane    Trichophyton Mentagrophytes                     100/25   31.250    Trichophyton Rubrum                     101/85   31.250    Microsporum Canis                     150/353  31.250    Candida. Albicans                     200/175  31.250    Aspergillus Niger                     500/284  31.250    Trichophyton Vaginalis                     111/216  15.625    erythro-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol    Trichophyton Mentagrophytes                     100/25   3.900    Trichophyton Rubrum                     101/85   15.625    Microsporum Canis                     150/353  3.900    Candida Albicans 200/175  1.950    Aspergillus Niger                     500/284  3.900    Trichophyton Vaginalis                     111/216  15.625    Cyclopirox    Trichophyton Mentagrophytes                     100/25   1.950    Trichophyton Rubrum                     101/85   1.950    Microsporum Canis                     150/353  1.950    Candida Albicans 200/175  1.950    Aspergillus Niger                     500/284  0.970    Trichophyton Vaginalis                     111/216  15.625    Clotrimazol    Trichophyton Mentagrophytes                     100/25   0.970    Trichophyton Rubrum                     101/85   0.240    Microsporum Canis                     150/353  0.060    Candida Albicans 200/175  3.900    Aspergillus Niger                     500/284  1.950    Trichophyton Vaginalis                     111/216  62.500    ______________________________________

Bacterial and fungal growth inhibition is achieved when the present1-alkyl-, 1-alkenyl-, and 1-alkynylaryl-2-amino-1,3-propanediols, andrelated compounds are administered to a subject requiring such treatmentas an effective oral, parenteral, intravenous, or topical, includingophthalimic administration, dose of from 0.01 to 100 mg/kg of bodyweight per day. A particularly effective amount is about 25 mg/kg ofbody weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set for hereinare exemplary only and that they do not, to any extent, limit the scopeor practice of the invention.

Compounds of the present invention include:

a. erythro-2-amino-1-(5-decyl-2-furyl)-1,3-dihydroxypropane;

b. erythro-2-amino-1-(5-decyl-3-isothiazolyl)-1,3-dihydroxypropane;

c. threo-2-amino-1-[5-decyl-3-(2-oxopyrrolyl)]-1,3-dihydroxypropane;

d.erythro-2-amino-1-[6-decyl-2-(4-methylpyridinyl)]-1,3-dihydroxypropane;

e.threo-2-amino-1-[6-decyl-2-(4-methoxypyridinyl)]-1,3-dihydroxypropane;

f.erythro-2-amino-1-[6-decyl-2-(5-chloropyridinyl)]-1,3-dihydroxypropane;

g.threo-2-amino-1-[6-decyl-2-(4-trifluoromethylpyridinyl)]-1,3-dihydroxypropane;

h.erythro-2-amino-1-[6-(5-phenylpentyl-2-pyridinyl)-1,3-dihydroxypropane;

i. erythro-2-amino-1-(2-decyl-4-thiazolyl)-1,3-dihydroxypropane;

j. erythro-2-amino-1-(2-decyl-4-oxazolyl)-1,3-dihydroxypropane;

k. erythro-2-methylamino-1-(5-decyl-2-thienyl)-1,3-dihydroxypropane

l. erythro-2-dimethylamino-1-(3-decyl)phenyl-1,3-dihydroxypropane;

m.erythro-2-(1,1-dimethylethoxy)carbonylamino-1-(2-dodecynyl-6-pyridinyl)-1,3-dihydroxypropane;

n. erythro-2-amino-1-(3-(1-decenyl)phenyl)-1,3-dihydroxypropane;

o. ethylerythro-2-methoxycarbonylamino-3-(2-dodecynyl-6-pyridinyl)-3-hydroxypropionate;

p. erythro-2-amino-1-(3-(1-decynyl)phenyl)-1,3-dihydroxypropane;

q. erythro-2-amino-1-(3-(1-undecynyl)phenyl)-1,3-dihydroxypropane;

r. erythro-2-amino-1-(4-(1-nonyl)-2-thienyl)-1,3-dihydroxypropane;

s. erythro-2-amino-1-(4-(1-dodecynyl)-2-thienyl)-1,3-dihydroxypropane;

t. erythro-2-amino-1-(4-(1-decyl)-2-thienyl)-1,3-dihydroxypropane;

u. erythro-2-amino-1-(5-nonyl-2-thienyl)-1,3-dihydroxypropane;

v. erythro-2-amino-1-(3-dodecyl-5-isoxazolyl)-1,3-dihydroxypropane;

w. erythro-2-amino-1-(3-decyl-5-isoxazolyl)-1,3-dihydroxypropane;

x. erythro-2-amino-1-(6-(1-dodecenyl)-2-pyridinyl)-1,3-dihydroxypropane;

y.erythro-2-amino-1-(3-(6-phenyl-1-hexynyl)phenyl)-1,3-dihydroxypropane;and

z. erythro-2-amino-1-(5-(6-phenylhexyl)-2-thienyl)-1,3-dihydroxypropane.

Effective amounts of the compounds of the present invention may beadministered topically to a subject in the form of sterile solutions,suspensions, ointments, creams, aerosols, or salves. The 1-alkyl-,1-alkenyl, and 1-alkynylaryl-2-amino-1,3-propanediols of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable acid orbase addition salts for purposes of stability, convenience orcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable acid addition salts include saltsof mineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,carboxysuccinic acid, citric acid and the like. Preferredpharmaceutically acceptable base addition salts include salts of alkalimetals, e.g. sodium or potassium, alkaline earth metals, e.g. calcium ormagnesium; or complex salts such as ammonium or substituted ammoniumsalts such as a mono-, di- or trialkylammonium salts or a mono, di- ortrihydroxyalkylammonium salts.

For the purpose of topical administration, the active compounds of theinvention may be incorporated into a solution, suspension, ointment,cream, gel, aerosol, or salve. These preparations should contain atleast 0.1% of active compound but may be varied to be between 0.05 andabout 20% of the weight thereof. The amount of active compound in suchcompositions is such that a suitable dosage will be obtained. Preferredtopically administered preparations should contain between 0.1 and 10%of active compound.

The topical compositions may also include the following components:water, fixed oils, polyethylene, glycols, glycerol, petroleum, stearicacid, beeswax, other synthetic solvents or mixtures thereof;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as α-tocopherol acetate; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphosphates; emulsifying agents such as polyoxyethylene monooleate andcoloring materials and adjuvants such as ferric oxide or talc. Thetopical preparation can be enclosed in tubes, bottles, or jars made ofmetal, glass or plastic.

The active compounds of the present invention may also be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The oral solutions or suspensions may also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1 6-(1-Dodecynyl)-2-pyridinecarboxaldehyde

To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) intetrahydrofuran (10 ml), was added sequentiallybis(triphenylphosphine)palladium(II) chloride (0.178 g), copper(I)iodide(0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). Thesolution was stirred at 40° C. overnight. The reaction mixture wascooled to room temperature, charged again withbis(triphenylphosphine)palladium (II) chloride (0.024 g), copper (I)iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml),and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. Thereaction mixture was again cooled and recharged as above, and heated at40° C. for 24 hrs. The cooled mixture was concentrated, taken up inethyl acetate (100 ml), washed with water and saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was taken up in ethyl acetate(100 ml) and filtered. The filtrate was combined with material from asimilar reaction run 1.43 g of the carboxaldehyde and proportionateamounts of the catalysts, 1-dodecyne, and solvent. The filtrate wasconcentrated. The residue was purified by flash chromatography using1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane aseluents. The appropriate fractions were collected and concentrated toyield 2.24 g (29%) of product, as an oil.

Analysis: Calculated for C₁₈ H₂₅ NO: 79.66% C 9.28% H 5.16% N Found:79.54% C 9.29% H 4.98% N

EXAMPLE 2erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide

Ethylerythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate(5.71 g) in dry tetrahydrofuran (75 ml) was slowly added to 2.0M lithiumborohydride/tetrahydrofuran (7.6 ml) at 0° under nitrogen, and themixture was stirred at room temperature overnight. The reaction mixturewas chilled, and 1:1 methanol:water (50 ml) was added slowly followed byglacial acetic acid (0.5 ml) until pH 6.5 was obtained. The reactionmixture was concentrated, and the residue azeotroped with methanol (4×40ml). The residue was slurried with 7.5% sodium bicarbonate solution (15ml) (pH 8.5), extracted into 3:1-trichloromethane:isopropanol andconcentrated. The appropriate fractions were collected and concentrated.The residue was purified by flash chromatography on silica gel elutingwith 49:1-ethyl acetate:methanol. The appropriate fractions werecollected and concentrated to give 4.74 g (93%) of product, mp 85°-87°C.

Analysis: Calculated for C₂₀ H₃₀ N₂ O₃ : 69.33% C 8.73% H 8.09% N Found:69.44% C 8.84% H 8.07% N

EXAMPLE 3erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetamide

N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(4.35 g), acetic anhydride (7.45 ml), triethylamine (16 ml), and4-dimethylaminopyridine (0.24 g) in dry tetrahydrofuran (80 ml) wasstirred at room temperature for 3 days. The reaction mixture wasevaporated, and the residue was warmed with methanol for 20 mins,reevaporated, and the residue was azeotroped with toluene. The residuewas taken up in trichloromethane, and 7.5% sodium bicarbonate solutionwas added until pH 8.5 was obtained. The mixture was extracted withtrichloromethane, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was combined with the residue(1.0 g) from a reaction, starting with 0.829 g of acetamide, andpurified by flash chromatography on silica gel eluting with1:1-hexane:ethyl acetate. The appropriate fractions were collected andconcentrated to yield 1.61 g (25%) of product.

Analysis: Calculated for C₂₄ H₃₄ N₂ O₅ : 66.95% C 7.96% H 6.51% N Found:66.65% C 8.04% H 6.36% N

EXAMPLE 4threo-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetamide

N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(4.35 g), acetic anhydride (7.45 ml), triethylamine (16 ml), and4-dimethylaminopyridine (0.24 g) in dry tetrahydrofuran (80 ml) wasstirred at room temperature for 3 days. The reaction mixture wasevaporated, and the residue was warmed with methanol for 20 min,reevaporated and azeotroped with toluene. The residue was taken up intrichloromethane, and 7.5% sodium bicarbonate solution was added untilpH 8.5 was obtained. The mixture was extracted with trichloromethane,dried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was combined with 1.0 g of the residue from another reaction(0.829 g of acetamide), and purified by flash chromatography on silicagel, eluting with 1:1-hexane:ethyl acetate to yield 1.02 g (15.9%) ofproduct, mp 59°-61° C.

Analysis: Calculated for C₂₄ H₃₄ N₂ O₅ : 66.95% C 7.96% H 6.51% N Found:67.21% C 7.83% H 5.92% N

EXAMPLE 5 Ethylerythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate

A 2:1-erythro:threo mixture of ethyl2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (10.0 g),1-decyne (5.01 g), bis(triphenylphosphine)palladium chloride (0.42 g)and cuprous iodide (0.06 g) in triethylamine (50 ml) was heated at50°-60° C. for 2.5 hrs. under nitrogen, and then at room temperatureovernight. The reaction mixture was evaporated, water was added, and themixture was extracted with ethyl acetate. The organic extract waspurified by flash chromatography on silica gel, eluting with 1:1hexane:ethyl acetate and collecting the appropriate fractions. Theappropriate fractions were evaporated. Recrystallization of the residuefrom ethyl acetate gave 7.8 g (66%) of the product, mp 97°-99° C.

Analysis: Calculated for C₂₂ H₃₂ N₂ O₄ : 68.01% C 8.30% H 7.21% N Found:68.23% C 8.28% H 7.22% N

EXAMPLE 6 Ethylthreo-2-acetamido-3-[6-(1-decynyl-2-pyridinyl]-3-hydroxypropionate

A mixture of ethyl2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (17.3 g, 97%erythro), 1-decyne (8.67 g), bis(triphenylphosphine)palladium chloride(0.73 g), cuprous iodide (0.10 g), and triethylamine (13.2 g) intetrahydrofuran (90 ml) was heated overnight at 50°-55° C., undernitrogen. The reaction mixture was evaporated, water was added, and themixture was extracted with ethyl acetate, and concentrated. The residuewas purified by flash chromatography on silica gel, eluting with1:1-hexane:ethyl acetate. The appropriate fractions were collected andevaporated. Recrystallization of the residue from 1:2-hexane:ethylacetate gave 14.7 g of 19:1-mixture erythro:threo-compounds, and fromthe mother liquors, 4.66 g of an 8:3 of mixture erythro:threo compounds.Flash chromatography of 2.63 g of the threo-enriched material on silicagel, eluting with 1:1-hexane:ethyl acetate, yielded 0.39 g (3.4%) ofproduct, mp 97°-99.5° C.

Analysis: Calculated for C₂₂ H₃₂ N₂ O₄ : 68.01% C 8.30% H 7.21% N Found:67.89% C 8.26% H 7.10% N

EXAMPLE 7erythro-N-{4-[6-(1-Decynyl)-2-pyridinyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide

N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (6.1g, 3:1-erythro:threo mixture), p-toluenesulfonic acid (3.7 g), and2,2-dimethoxypropane (43 ml) in dichloromethane (115 ml) were stirred atroom temperature overnight, under nitrogen. The reaction mixture wasextracted with 0.5M sodium bicarbonate solution and water, dried overanhydrous magnesium sulfate, filtered, and the filtrate was evaporated.The residue was chromatographed on silica gel, eluting with2:1-hexane:ethyl acetate to give 2.4 g (35%) of product, as an oil.

Analysis: Calculated for C₂₃ H₃₄ N₂ O₃ : 71.47% C 8.87% H 7.25% N Found:71.14% C 9.12% H 7.13% N

EXAMPLE 8threo-N-{4-[6-(1-Decynyl)-2-pyridinyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide

N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide (6.1g, 3:1-erythro:threo mixture), p-toluenesulfonic acid (3.7 g), and2,2-dimethoxypropane (43 ml) in dichloromethane (115 ml) were stirred atroom temperature overnight, under nitrogen. The reaction mixture waswashed with 0.5M sodium bicarbonate solution and water, dried overanhydrous magnesium sulfate, filtered, and the filtrate was evaporated.The residue was chromatographed twice on silica gel, eluting with2:1-hexane:ethyl acetate to 1:1-hexane:ethyl acetate to give 0.76 g(11%) of product, as an oil.

Analysis: Calculated for C₂₃ H₃₄ N₂ O₃ : 71.47% C 8.87% H 7.25% N Found:71.15% C 8.91% H 7.06% N

EXAMPLE 9 Ethylerythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate

A solution of 6-(1-dodecynyl)-2-pyridinecarboxaldehyde (5.51 g),acetamidomalonic acid monoethyl ester (3.78 g), and triethylamine (2.8ml) in dry tetrahydrofuran (30 ml) was stirred at room temperatureovernight, under nitrogen. The reaction mixture was evaporated, and theresidue was purified on a silica gel column eluting with1:1-hexane:ethyl acetate to give 7.46 g (89.6%) of product(10:1-erythro:threo mixture). This product was combined with 7.40 g froma prior reaction run on the same scale, and the combined material wasrecrystallized from 2:1-ethyl acetate:hexane to give 9.62 g (57.7%) ofthe analytically pure product, mp 86°-87.5° C.

Analysis: Calculated for C₂₄ H₃₆ N₂ O₄ : 69.20% C 8.71% H 6.72% N Found:69.40% C 8.72% H 6.68% N

EXAMPLE 10 Ethylerythro-2-acetamido-3-[6-(1-hexynyl)-2-pyridinyl]-3-hydroxypropionate

An 11:1-erythro:threo mixture of ethyl2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (24.9 g),1-hexyne (7.39 g), triethylamine (19.0 g),bis(triphenylphosphine)palladium chloride (1.05 g) and cuprous iodide(0.14 g) in dry tetrahydrofuran (100 ml) was heated at 55° C. for 6 hrs,under nitrogen. Additional 1-hexyne (6.2 g), triethylamine (7.6 g),bis(triphenylphosphine)palladium chloride (0.53 g), and cuprous iodide(0.07 g) were added at room temperature and the reaction mixture washeated an additional 5.5 hrs. The mixture was evaporated, water wasadded, and the mixture was extracted with ethyl acetate. The extract wasflash chromatographed (silica gel, 1:1-hexane:ethyl acetate). Theappropriate fractions were collected and evaporated. Recrystallizationof the residue from 1:1-hexane:ethyl acetate provided 3.8 g (15%) ofproduct, 87°-88° C.

Analysis: Calculated for C₁₈ H₂₄ N₂ O₄ : 65.04% C 7.28% H 8.43% N Found:65.19% C 7.31% H 8.37% N

EXAMPLE 11erythro-N-{1,3-Diacetyloxy-1-[6-(1-hexynyl)-2-pyridinyl]-2-propanyl}acetamide

To ethylerythro-2-acetamido-3-[6-(1-hexynyl)-2-pyridinyl]-3-hydroxypropionate(16.0 g) in dry tetrahydrofuran (140 ml) was added 2.0M lithiumborohydride:tetrahydrofuran (24 ml) at 0° C., with stirring, undernitrogen. After the addition was complete, the mixture was allowed towarm to room temperature and was stirred overnight. The reaction mixturewas chilled and 1:1-methanol:water (80 ml) was added slowly followed byacetic acid (2.8 ml) until a pH of 6.8 was obtained. The reactionmixture was stirred for 1 hr and evaporated. The residue was azeotropedseveral times with methanol. A 7.5% sodium bicarbonate solution wasadded to the residue until a pH of 8.5 was obtained, and the mixture wasextracted with 3:1 trichloromethane:isopropanol and concentrated. Theresidue was flash chromatographed on silica gel eluting with 1%methanol:ethyl acetate to give 13.2 g (94%) oferythro-N-{1-[6-(1-hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide.

erythro-N-{1-[6-(1-hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(10.3 g), acetic anhydride (21.8 g), triethylamine (32.4 g), and4-dimethylaminopyridine (0.44 g) in tetrahydrofuran (150 ml) was stirredat room temperature overnight. The reaction mixture was evaporated,methanol was added to the residue, and the solution was warmed at 50° C.for 15 min. The mixture was evaporated. The residue was dissolved inchloroform, and 7.5% sodium bicarbonate solution was added until a pH 8was obtained. The mixture was extracted with chloroform. The extract wasdried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was flash chromatographed, eluting with1:1-hexane:ethyl acetate to yield 7.3 (55%) of product, mp 97°-99° C.

Analysis: Calculated for C₂₀ H₂₆ N₂ O₅ : 64.16% C 7.00% H 7.48% N Found:64.17% C 7.00% H 7.44% N

EXAMPLE 12erythro-N-{1-[6-(1-Hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide

erythro-N-{1,3-Diacetyloxy-1-[6-(1-hexynyl)-2-pyridinyl]-2-propanyl}acetamide(6.7 g) and potassium carbonate (3.3 g) in methanol (100 ml) was stirredfor 40 min. The precipitate was collected, and the filtrate wasevaporated. A 7.5% sodium bicarbonate solution was added to pH 8.5, andthe mixture was extracted with 3:1-trichloromethane:2-propanol, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. Recrystallization of the residue from 1:1-hexane:ethylacetate gave 4.6 g (88%) of product, mp 75°-77° C.

Analysis: Calculated for C₁₆ H₂₂ N₂ O₃ : 66.19% C 7.64% H 9.65% N Found:65.99% C 7.55% H 9.65% N

EXAMPLE 13 Ethylerythro-2-acetamido-3-hydroxy-3-[6-(1-octynyl)-2-pyridinyl]propionate

A mixture of an 11:1-erythro:threo mixture of ethyl2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (24.9 g),1-octyne (9.9 g), triethylamine (19.0 g),bis(triphenylphosphine)palladium chloride (1.05 g) and cuprous iodide(0.14 g) in dry tetrahydrofuran (100 ml) was heated at 55° C. for 6 hrs,under nitrogen. Additional 1-octyne (4.1 g), triethylamine (3.8 g),bis(triphenylphosphine)palladium chloride (0.53 g), and cuprous iodide(0.07 g) were added at room temperature, and the reaction mixture washeated an additional 4 hrs. The mixture was evaporated, water was added,and the mixture was extracted with ethyl acetate. The solution was flashchromatographed on silica gel eluting with 1:1-hexane:ethyl acetate. Thefractions, enriched in the erythro isomer, were evaporated and theresidue was recrystallized from 1:1-isopropanol:water to give 3.2 g(12%) of product, mp 81°-83° C.

Analysis: Calculated for C₂₀ H₂₈ N₂ O₄ : 66.64% C 7.83% H 7.77% N Found:66.62% C 7.77% H 7.75% N

EXAMPLE 14erythro-N-{1,3-Dihydroxy-1-[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide

To ethylerythro-2-acetamido-3-hydroxy-3-[6-(1-octynyl)-2-pyridinyl]propionate(9.02 g) in dry tetrahydrofuran (80 ml) was added slowly 2.0M lithiumborohydride:tetrahydrofuran (12.5 ml) at 0°, under nitrogen. The mixturewas stirred at room temperature overnight, chilled, and1:1-methanol:water was added slowly followed by glacial acetic acid (1.5ml) in 1:1-methanol:water (15 ml) until pH 6.8 was obtained. Thesolution was stirred at room temperature for 1.5 hrs, evaporated, andthe residue was azeotroped with methanol (4×40 ml). The residue wasslurried with 7.5% sodium bicarbonate solution (25 ml) (pH 8.5),saturated sodium chloride solution (25 ml), extracted with3:1-trichloromethane:2-propanol, and concentrated. The residue was flashchromatographed on silica gel, eluting with ethyl acetate:0.5% methanol.The appropriate fractions were collected and evaporated. The residue wasrecrystallized (3 times) from ethyl acetate to give 1.24 g (15.6%) ofproduct, mp 81°-83° C.

Analysis: Calculated for C₁₈ H₂₆ N₂ O₃ : 67.90% C 8.23% H 8.80% N Found:68.03% C 7.97% H 8.70% N

EXAMPLE 15 Ethylerythro-2-acetamido-3-[6-(1-hexadecynyl)-2-pyridinyl]-3-hydroxypropionate

A solution of 6-(1-hexadecynyl)-2-pyridinecarboxaldehyde (17.4 g),acetamidomalonic acid monoethyl ester (10.6 g), and triethylamine (5.4ml) in dry tetrahydrofuran (85 ml) was stirred at room temperature for 3days, under nitrogen. The reaction mixture was evaporated and theresidue was dissolved in ethyl acetate. The solution was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waspurified on a silica gel column, eluting with 2:1- to 1:1-hexane:ethylacetate. The appropriate fractions were collected and evaporated. Theresidue was recrystallized from ethanol and then 85% ethanol to give12.8 g (50.9%) of product, mp 82.5°-84° C.

Analysis: Calculated for C₂₈ H₄₄ N₂ O₄ : 71.15% C 9.38% H 5.93% N Found:70.86% C 9.18% H 5.82% N

EXAMPLE 16erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate(20.3 g) in dry tetrahydrofuran (250 ml) 2.0M lithiumborohydride:tetrahydrofuran (30 ml) was added at 0°, under nitrogen. Thereaction mixture was stirred at room temperature overnight. The mixturewas chilled and 1:1-methanol:water (100 ml) was added slowly followed byglacial acetic acid (3.5 ml) in 1:1-methanol:water (50 ml) until a pH of6.5 was obtained. The solution was stirred at room temperature for 2hrs, the solvents were evaporated, and the residue was azeotroped withmethanol (5×100 ml). The residue was slurried with 7.5% sodiumbicarbonate solution (65 ml) (pH 8.5), extracted into3:1-chloroform:2-propanol, and concentrated. The residue was flashchromatographed on silica gel, eluting with 0.5% -methanol:ethylacetate. The appropriate fractions were collected and evaporated.Recrystallization of the residue from hexane:ethyl acetate/1:1 gave 15.5g (85.0%) of product, mp 86°-88° C.

Analysis: Calculated for C₂₂ H₃₄ N₂ O₃ : 70.55% C 9.15% H 7.48% N Found:70.78% C 9.35% H 7.49% N

EXAMPLE 17 Ethylerythro-2-acetamido-3-(6-decyl-2-pyridinyl)-3-hydroxypropionate

Ethylerythro-2-acetamido-3-[6-(1-decynyl)-2-pyridinyl]-3-hydroxypropionate(2.7 g) in ethanol (65 ml) was reduced using 5% palladium-on-charcoal(0.7 g) in a Parr hydrogenator at 40 psi of hydrogen. After 2.5 hrs, thecatalyst was collected, the filtrate was evaporated, and the residue wasrecrystallized from ethyl acetate to give 2.11 g (77.6%) of product, mp67°-68.5° C.

Analysis: Calculated for C₂₂ H₃₆ N₂ O₄ : 67.32% C 9.24% H 7.14% N Found:66.96% C 9.13% H 7.08% N

EXAMPLE 18erythro-N-[1-(6-Decyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide

erythro-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}-acetamide(4.0 g) in ethanol (100 ml) was reduced using 5% palladium-on-charcoal(0.1 g) in a Parr hydrogenator at 40 psi of hydrogen. After two hrs, thecatalyst was collected, the solvent was evaporated, and the residue wasrecrystallized from ethyl acetate to give 3.69 g (91%) of product, mp94°-96° C.

Analysis: Calculated for C₂₀ H₃₄ N₂ O₃ : 68.54% C 9.78% H 7.99% N Found:68.36% C 9.72% H 7.94% N

EXAMPLE 19 threo-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane

threo-N-{1-[6-(1-Decynyl)-2-pyridinyl]-1,3-diacetyloxy-2-propanyl}acetamide(1.0 g) in ethanol (55 ml) was reduced using 5% palladium-on-charcoal(0.06 g) in a Parr hydrogenator at 40 psi of hydrogen. After two hrs,the catalyst was collected, and the solvent was evaporated to give 0.95g (94%) ofthreo-N-[3-(6-decyl-2-pyridinyl)-1,3-diacetyloxy-2-propanyl]acetamide.

The acetamide (0.95 g), hydrazine hydrate (40 ml), and ethanol (20 ml)was heated under reflux for 25 hrs., under nitrogen. The reactionmixture was cooled, water (30 ml) was added, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel eluting with 980:20:2- to970:30:2-trichloromethane:methanol:2N ammonium hydroxide. Theappropriate fractions were collected and evaporated. The residue wasdissolved in ethyl acetate, washed with half-saturated sodium chloridesolution, dried, filtered, and the filtrate was evaporated to give 0.50g (72%) of product, mp 76°-78° C.

Analysis: Calculated for C₁₈ H₃₂ N₂ O₂ : 70.09% C 10.46% H 9.08% NFound: 70.02% C 10.63% H 8.85% N

EXAMPLE 20 erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-dihydroxypropane

erythro-N-[1-(6-Decyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide(6.0 g), hydrazine hydrate (60 ml), and ethanol (15 ml) were refluxedfor 20 hrs., under nitrogen. The reaction mixture was cooled, water (75ml) was added, and the mixture was extracted with ethyl acetate. Theethyl acetate layers were washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was combined with 1.44 g from twoother experiments, and was chromatographed on silica gel eluting with950:50:3- to 900:100:5- trichloromethane:methanol:2N ammonium hydroxide.The appropriate fractions were collected and evaporated. The residue wasdissolved in ethyl acetate (150 ml) and the solution was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated to give 5.60 g (79%)of product, mp 52°-55° C.

Analysis: Calculated for C₁₈ H₃₂ N₂ O₂ : 70.09% C 10.46% H 9.08% NFound: 69.63% C 10.29% H 8.87% N

EXAMPLE 21 Ethylerythro-2-acetamido-3-(6-dodecyl-2-pyridinyl)-3-hydroxypropionate

Ethylerythro-2-acetamido-3-[6-(1-dodecynyl)-2-pyridinyl]-3-hydroxypropionate(2.0 g) in ethanol (80 ml) containing of 5% palladium-on-carbon (0.06 g)was reduced in a Parr hydrogenator at 40 psi of hydrogen. After two hrs,the catalyst was filtered, the filtrate was evaporated, and the residuewas recrystallized from ethyl acetate to give 1.42 g (70.3%) of product,mp 71°-73° C.

Analysis: Calculated for C₂₄ H₄₀ N₂ O₄ : 68.54% C 9.59% H 6.66% N Found:68.74% C 9.46% H 6.69% N

EXAMPLE 22erythro-N-[1-(6-Dodecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide

erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(6.05 g) in ethanol (120 ml) containing 5% palladium-on-carbon (0.15 g)was reduced in a Parr hydrogenator at 30 psi of hydrogen. After two hrs,the catalyst was filtered, the filtrate was evaporated, and the residuewas recrystallized from ethyl acetate to give 5.90 g (96.4%) of product,mp 99°-100.5° C.

Analysis: Calculated for C₂₂ H₃₈ N₂ O₃ : 69.80% C 10.12% H 7.40% NFound: 69.71% C 10.37% H 7.34% N

EXAMPLE 23 erythro-2-Amino-1-(6-dodecyl-2-pyridinyl)-1,3-propanediol

erythro-N-[1-(6-Dodecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide(3.8 g), hydrazine hydrate (35 ml), and ethanol (20 ml) were refluxedunder nitrogen for 24 hrs. The reaction mixture was cooled, water (50ml) was added, and the mixture was extracted with chloroform (3×65 ml).The extracts were washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. The residue was chromatographed on silica gel, eluting with950:50:3-chloroform:methanol:2N ammonium hydroxide. The residue wasdissolved in ethyl acetate and the solution was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated to give 2.10 g (62%)of product, mp 61°-64° C.

Analysis: Calculated for C₂₀ H₃₆ N₂ O₂ : 71.38% C 10.78% H 8.32% NFound: 71.04% C 10.95% H 8.07% N

EXAMPLE 24erythro-N-[1-(6-Hexyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide

erythro-N-{1-[6-(1-Hexynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(5.80 g) in ethanol (125 ml) was hydrogenated using 0.15 g of 5%palladium-on-carbon in a Parr system at 40 psi. After 2.5 hours, thecatalyst was collected, the filtrate was evaporated, and the residue wasrecrystallized from ethyl acetate to give 5.2 g (88.6%) of product, mp75°-76.5° C.

Analysis: Calculated for C₁₆ H₂₆ N₂ O₃ : 65.28% C 8.90% H 9.52% N Found:65.18% C 8.78% H 9.50% N

EXAMPLE 25N,O,O-Tribenzyloxycarbonyl-erythro-2-amino-1-(6-decyl-2-pyridinyl)-1,3-propanediol

erythro-2-Amino-1-(6-decyl-2-pyridinyl)-1,3-propanediol (1.50 g),N-benzyloxycarbonyloxysuccinimide (4.00 g) and triethylamine (2.23 ml)in dry tetrahydrofuran (60 ml) was stirred at room temperature for 9days, under nitrogen. Additional N-benzyloxycarbonyloxysuccinimide (4.00g) was added and stirring was continued for 3 days. The reaction mixturewas evaporated. The residue was dissolved in ethyl acetate and thesolution was washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and the filtrate was evaporated.The residue was purified by flash chromatography (silica gel, 9:1hexane:ethyl acetate). The appropriate fractions were collected andevaporated to give 1.87 g (54%) of product.

Analysis: Calculated for C₄₂ H₅₀ N₂ O₈ : 70.96% C 7.09% H 3.94% N Found:71.00% C 6.92% H 3.77% N

EXAMPLE 26 Ethylerythro-2-acetamido-3-hydroxy-3-[3-(1-undecynyl)phenyl]propionate

To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) intriethylamine (120 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture wasstirred in the dark at 55° C. for 6 hrs, under nitrogen. After coolingto room temperature, the reaction mixture was diluted with ethyl acetateand filtered. The filtrate was washed with water and saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated to yield 45.8 g of3-(1-undecynyl)benzaldehyde, as an oil.

A solution of 3-(1-undecynyl)benzaldehyde (23.0 g), acetamidomalonicacid monoethyl ester (15.1 g), and triethylamine (11.2 ml) in drytetrahydrofuran (150 ml) was stirred at room temperature for 48 hrs,under nitrogen. Additional acetamidomalonic acid monoethyl ester (7.6 g)and triethylamine (5.6 ml) were added and stirring was continued for 72hrs. The reaction mixture was evaporated and the residue was purified ona silica gel column, eluting with 2:1-hexane:ethyl acetate to give 13.0g (41%) of product. The product was dissolved in warm 3:2-ethanol:waterand cooled. The precipitate was collected. The filtrate was concentratedand the residue was recrystallized from cyclohexane to give theanalytical sample, mp 69°-71° C.

Analysis: Calculated for C₂₄ H₃₅ NO₄ : 71.79% C 8.79% H 3.49% N Found:71.81% C 8.72% H 3.51% N

EXAMPLE 27 Ethylerythro-2-acetamido-3-[3-(1-dodecynyl)phenyl]-3-hydroxypropionate

To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne intriethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultantmixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and filtered. The filtrate was washed with water andsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and concentrated to yield 37.7 g3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.

A solution of 3-(1-dodecynyl)benzaldehyde (7.6 g), acetamidomalonic acidmonoethyl ester (5.1 g), and triethylamine (3.8 ml) in drytetrahydrofuran (35 ml) was stirred at room temperature for 48 hrs,under nitrogen. Additional acetamidomalonic acid monoethyl ester (2.6 g)and triethylamine (1.9 ml) were added and stirring for 72 hr. Themixture was evaporated, and the residue was purified on a silica gelcolumn, eluting with 2:1-hexane:ethyl acetate to give 4.8 g (43%) ofproduct. The product was dissolved in warm 3:2-ethanol:water and cooled.The precipitate was collected. The filtrate was concentrated and theresidue was recrystallized from 1:2-ethyl acetate:hexane to provide theanalytical sample, mp 80°-82° C.

Analysis: Calculated for C₂₅ H₃₇ NO₄ : 72.26% C 8.97% H 3.37% N Found:72.34% C 8.74% H 3.38% N

EXAMPLE 28cis-erythro-N-{1-[6-(1-Dodecenyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide

erythro-N-{1-[6-(1-Dodecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(2.05 g) in ethanol (55 ml), 5% palladium-on-barium sulfate (0.02 g),and 0.04 g of quinoline was hydrogenated at atmospheric pressure untilone equivalent of hydrogen (ca. 123 ml) was taken up. The catalyst wasfiltered, the filtrate was evaporated, and the residue (2.1 g) wascombined with residue (3.5 g) from similar reactions. The combinedresidues were chromatographed on silica gel eluting with 1:2- to1:4-hexane:ethyl acetate to give 1.58 g (28%) of product, mp 96°-98° C.

Analysis: Calculated for C₂₂ H₃₆ N₂ O₃ : 70.18% C 9.64% H 7.44% N Found:70.17% C 9.67% H 7.43% N

EXAMPLE 29 5-(1-Dodecynyl)-2-thiophenecarboxaldehyde

A solution of 1-dodecyne (28.7 g), 5-bromo-2-thiophenecarboxaldehyde(30.0 g) and triethylamine (47.7 g) in dry tetrahydrofuran (75 ml) wasdegassed and stirred at room temperature under a nitrogen atmosphere.bis(Triphenylphosphine)palladium(II)chloride (two mole percent) followedby copper(I)iodide (one mole percent) was added to the mixture. Themixture was degassed again and stirred at room temperature for threehrs, under nitrogen. The precipitate was collected and washed with ethylacetate, and the filtrate was evaporated. The residue was distilled in akugelrohr (oven temp=175° C./0.1 mm Hg) to give 27.1 g (62%) of product,as a oil. A portion of the oil was purified by flash chromatography(silica; 7:3-hexane-dichloromethane) and dried at 50° C. under vacuumfor three hrs to give the analytical sample

Analysis: Calculated for C₁₇ H₂₄ OS: 73.86% C 8.75% H Found: 73.86% C8.72% H

EXAMPLE 30 Ethylerythro-2-acetamido-3-[5-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate

A slurry of 5-dodecynyl-2-thiophenecarboxaldehyde (31.8 g),acetamidomalonic acid monoethyl ester (21.7 g), and dry tetrahydrofuran(150 ml) was degassed and cooled to 0° C. Triethylamine (5% excess) wasadded, the solution was degassed, and the reaction mixture was stirredat room temperature for 2 days, under nitrogen. Additionalacetamidomalonic acid monoethyl ester (21.7 g) and triethylamine (5%excess) were added, and the reaction mixture was stirred at roomtemperature for 5 days, under nitrogen. The mixture was evaporated, andthe residue was purified by flash chromatography (silica, 1:1-ethylacetate:hexanes). The appropriate fractions were collected andevaporated. The residue was recrystallized from ether and from ethylacetate-hexane to give 29.5 g (61%) of product, mp 81°-83° C.

Analysis: Calculated for C₂₃ H₃₅ NO₄ S: 65.53% C 8.37% H 3.32% N Found:65.36% C 8.25% H 3.30% N

EXAMPLE 31erythro-N-[1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl]acetamide

A solution of ethylerythro-2-acetamido-3-[5-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate(15.0 g) in dry tetrahydrofuran (150 ml) was stirred at 0° C., undernitrogen, as 2M lithium borohydride in tetrahydrofuran (22.3 ml) wasadded dropwise. The reaction mixture was stirred at room temperature for3 days, under nitrogen. The pH of the mixture was adjusted to 6 withglacial acetic acid, and the mixture was evaporated. The residue wasdiluted with water (100 ml) and extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous magnesium sulfate,filtered, and the filtrate was evaporated. The residue was purified byflash chromatography (silica, 1-5% methanol-ethyl acetate). Theappropriate fractions were collected and evaporated. The residue wasrecrystallized from ethyl acetate-hexane to give 9.6 g (71%) of product,mp 83°-85° C.

Analysis: Calculated for C₂₁ H₃₃ NO₃ S: 66.45% C 8.76% H 3.69% N Found:66.47% C 8.53% H 3.75% N

EXAMPLE 32 erythro-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl]acetamide(3.00 g), 2N sodium hydroxide solution (100 ml) and 95% ethanol (50 ml)was stirred at 65° C. overnight. After cooling to room temperature, themixture was evaporated, and the residue was diluted with sodiumbicarbonate solution (250 ml). The mixture was extracted with3:1-chloroform:isopropanol and the combined organic layers were driedanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was purified by flash chromatography (silica gel,90:9:1-dichloromethane:methanol:ammonium hydroxide). The appropriatefractions were collected and evaporated. The residue was crystallizedfrom ethyl acetate:hexane to give 1.4 g (53%) of product, mp 77°-78° C.

Analysis: Calculated for C₁₉ H₃₁ NO₂ S: 67.61% C 9.26% H 4.15% N Found:67.61% C 8.63% H 4.16% N

EXAMPLE 33erythro-N-[1-[5-(1-Dodecyl)-2-thienyl]-1,3-dihydroxy-2-propanyl]acetamide

A mixture oferythro-N-[1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(8.00 g), 5% palladium-on-carbon (400 mg), and absolute ethanol (500 ml)was shaken on a Parr hydrogenator under 50 psi of hydrogen for threehrs. The catalyst was collected. Fresh catalyst (400 mg) was added tothe filtrate and the mixture was shaken under 50 psi of hydrogenovernight. The mixture was filtered through a bed of celite, and thefilter cake washed with ethanol. The filtrate was evaporated, and theresidue was recrystallized from ethyl acetate to give 7.3 g (90%) ofproduct, m.p. 104°-106° C.

Analysis: Calculated for C₂₁ H₃₇ NO₃ S: 65.75% C 9.72% H 3.65% N Found:65.45% C 9.58% H 3.67% N

EXAMPLE 34 erythro-2-Amino-1-[5-(1-dodecyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[3-[5-(1-dodecyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(3.00 g), hydrazine monohydrate (35 ml) and absolute ethanol (25 ml) wasstirred at 70° C. for 48 hrs, under nitrogen. The reaction mixture wascooled to room temperature, poured into 300 ml of dilute sodiumbicarbonate solution (300 ml), and extracted with chloroform. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was purified byflash chromatography (silica; 90:9:1-dichloromethane:methanol:ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was recrystallized from ethyl acetate:hexane to give 1.4 g (52%)of product, m.p. 89°-90° C.

Analysis: Calculated for C₁₉ H₃₅ NO₂ S: 66.81% C 10.33% H 4.10% N Found:66.48% C 10.37% H 4.11% N

EXAMPLE 35 Ethylerythro-2-acetamido-3-(3-dodecyl-5-isoxazolyl)-3-hydroxypropionate

A mixture of 3-dodecyl-5-isoxazolecarboxaldehyde (5.72 g) andacetaminomalonic acid monoethylester (4.06 g) in dry tetrahydrofuran (75ml) was cooled to 0°, with stirring, and triethylamine (2.29 g) wasadded. The reaction mixture was allowed to warm to room temperature andwas stirred for 16 hrs. The solution was evaporated and the residue waspurified by flash chromatography (silica gel, 2:1-ethylacetate:hexanes). The appropriate fractions were collected andevaporated. Recrystallization of the residue from ethyl acetate:hexanegave 4.65 g (52.6%) of product, mp 87°-89° C.

Analysis: Calculated for C₂₂ H₃₈ N₂ O₅ : 64.36% C 9.33% H 6.82% N Found:64.55% C 9.08% H 6.76% N

EXAMPLE 36erythro-N-[1-[3-(1-Dodecyl)-5-isoxazolyl]-1,3-dihydroxy-2-propyl]acetamide

To a solution of freshly prepared calcium borohydride (0.61 g) (fromcalcium hydride and borane-dimethyl sulfide) in dry tetrahydrofuran (70ml) was added a solution of ethylerythro-2-acetamido-3-(3-dodecyl-5-isoxazolyl)-3-hydroxypropionate (2.4g) in dry tetrahydrofuran (20 ml). The reaction mixture was stirred atroom temperature for 3 hrs. The reaction was quenched with90:10:5-mixture of water, methanol, acetic acid, and extracted withchloroform. The solution was evaporated and the residue wasrecrystallized twice from ethyl acetate-hexane to give 1.23 g (57.1%) ofproduct, mp 88°-90° C.

Analysis: Calculated for C₂₀ H₃₆ N₂ O₄ : 65.19% C 9.85% H 7.60% N Found:65.17% C 9.60% H 7.60% N

EXAMPLE 37 Ethylerythro-2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate

A solution of 6-bromo-2-pyridinecarboxaldehyde (5.6 g), acetamidomalonicacid monoethyl ester (5.67 g), and triethylamine (4.2 ml) in drytetrahydrofuran (40 ml) was stirred at room temperature overnight, undernitrogen. The reaction mixture was evaporated and the mixture waspurified on a silica gel column, eluting with 1:1-hexane:ethyl acetateto give 7.9 g (80%) of product as a mixture of two diastereomers.Recrystallization from toluene, followed by ethyl acetate gave 2.15 g(21.6%) of the erythro product, mp 98°-100° C.

Analysis: Calculated for C₁₂ H₁₅ BrN₂ O₄ : 43.52% C 4.57% H 8.46% NFound: 43.56% C 4.53% H 8.42% N

EXAMPLE 38erythro-N-[1-(6-Bromo-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide

To a 2:1-erythro:threo mixture of ethyl2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (11.4 g) in drytetrahydrofuran (60 ml) was added slowly 2.0M lithiumborohydride/tetrahydrofuran (20.6 ml) at 0°, under nitrogen, and themixture was stirred at room temperature overnight. The reaction mixturewas chilled, and 1:1-methanol:water (100 ml) was added slowly followedby glacial acetic acid (2 ml) until pH 6.5 was obtained. The mixture wasevaporated and the residue azeotroped with methanol (6×50 ml). Theresidue was slurried with 7.5% sodium bicarbonate solution (40 ml) (pH8.5), extracted with 3:1-trichloromethane:isopropanol, filtered, and thefiltrate was concentrated. The residue was flash chromatographed onsilica gel eluting with 19:1-ethyl acetate:methanol to give 8.9 (93.7%)of product. Recrystallization from ethanol gave the analytical sample ofthe erythro-diastereomer, mp 134.5°-136.5° C.

Analysis: Calculated for C₁₀ H₁₃ BrN₂ O₃ : 41.54% C 4.53% H 9.69% NFound: 41.64% C 4.54% H 9.64% N

EXAMPLE 39 6-(1-Hexadecynyl)-2-pyridinecarboxaldehyde

A solution of 6-bromo-2-pyridinecarboxaldehyde (12.3 g), 1-hexadecyne(16.1 g), triethylamine (20.0 g),bis(triphenylphosphine)palladium(II)chloride (0.92 g), andcopper(I)iodide (0.13 g) in dry tetrahydrofuran (55 ml) was heated at50° C. for 29 hrs, under nitrogen. The reaction mixture was cooled toroom temperature, filtered, and the filter cake was washed with ethylacetate. The filtrate was evaporated and the residue was taken up inethyl acetate (100 ml). The mixture was washed with 1:1-water:saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and the filtrate was evaporated. The residue was flashchromatographed on silica gel, eluting with 1% ethyl acetate:hexanes.The appropriate tractions were collected and evaporated. The residue wasdissolved in ethyl acetate and the solution was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated to give 11.5 g(53.5%) of product, mp 38.5°-40° C.

Analysis: Calculated for C₂₂ H₃₃ NO: 80.68% C 10.16% H 4.28% N Found:80.44% C 10.00% H 4.30% N

EXAMPLE 40 3-(1-Dodecyl)-5-isoxazolemethanol

To a solution of 1-nitrotridecane (10.5 g) and O-trimethylsilyl-propynol(5.88 g) in dry benzene (100 ml) was added dropwise a solution offreshly distilled phenylisocyanate (10.9 g) and triethylamine (5.56 g)in dry benzene (40 ml) at 40° C., with mechanical stirring. The mixturewas heated to 60° C. for 3.5 hr, cooled, and filtered. The filtrate wasevaporated, taken up in tetrahydrofuran (300 ml) and 1.0Mtetrabutylammonium fluoride (8 ml) was added. After 30 mins, the mixturewas evaporated and the residue was purified by flash chromatography(silica gel, 2% methanol:dichloromethane). The appropriate fractionswere collected and evaporated to give 10.5 g (86%) of product, mp61°-63° C.

Analysis: Calculated for C₁₆ H₂₉ NO₂ : 71.87% C 10.93% H 5.24% N Found:71.92% C 11.10% H 5.19% N

EXAMPLE 41 3-(1-Dodecyl)-5-isoxazolecarboxaldehyde

A solution of oxalyl chloride (28.8 ml) in dry dichloromethane (100 ml)was cooled to -60° C. and a solution of dimethylsulfoxide (8.9 ml) indichloromethane (30 ml) was added, followed by a slurry of3-(1-dodecyl)-5-isoxazolemethanol (14.0 g) in dry dichloromethane (200ml). The mixture was stirred at -60° C. for 1 hr, quenched withtriethylamine (87 ml) and allowed to warm to room temperature. Thesolution was poured into water (300 ml) and extracted withdichloromethane. The organic phases were washed with dilute citric acidsolution, dried, filtered, and the filtrate was evaporated. The residuewas passed through a short pad of silica gel using dichloromethane asthe eluent. The solution was evaporated and the residue wasrecrystallized from ether-hexane to give 11.5 g (78%) of product, mp53°-54° C.

Analysis: Calculated for C₁₆ H₂₇ NO₂ : 72.41% C 10.25% H 5.28% N Found:72.22% C 10.59% H 5.24% N

EXAMPLE 42erythro-N-{1-[6-(1-Hexadecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide

To ethyl erythro-2-acetamido-3-{6-(1-hexadecynyl)2-pyridinyl]-3-hydroxypropionate (11.1 g), in tetrahydrofuran (100 ml) dry was added slowly2.0M lithium borohydride/tetrahydrofuran (11.8 ml) at 0° under nitrogen.The reaction mixture was stirred at ambient temperature for 2.5 hrs,chilled, and 1:1-methanol:water (60 ml) and glacial acetaic acid (1.4ml) was added slowly until a pH of 6.5 was obtained. The mixture wasthen stirred at ambient temperature for 0.5 hr and evaporated. Theresidue was azeotroped with methanol (4×40 ml), slurried with 7.5%sodium bicarbonate solution (25 ml) (pH 8.5), and the mixture wasextracted with 3:1-chloroform:2-propanol. The solution was concentratedand the residue was flash chromatographed on silica gel, eluting with99:1-ethyl acetate:methanol. The appropriate fractions were collectedand evaporated. Recrystallization gave 8.57 g (84.4%) of product, mp88°-90° C.

Analysis: Calculated for C₂₆ H₄₂ N₂ O₃ : 72.52% C 9.83% H 6.51% N Found:72.55% C 9.46% H 6.54% N

EXAMPLE 43erythro-N-[1,3-Diacetyloxy-1-(6-hexadecyl-2-pyridinyl)-2-propanyl]acetamide

A mixture ofN-{1-[6-(1-hexadecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide.(7.26 g, 5:2-erythro:threo mixture), acetic anhydride (10.5 g),triethylamine (15.5 g), and 4-dimethylaminopyridine (0.21 g), intetrahydrofuran (100 ml) was stirred at ambient temperature overnight.The reaction mixture was evaporated, methanol was added, and the mixturewas warmed at 50° C. for 20 min, and then was concentrated. A solutionof 7.5% sodium bicarbonate solution was added to the residue until a pHof 8.5 was obtained. The mixture was extracted with chloroform. Theorganic extract was dried over anhydrous magnesium sulfate, filtered andthe filtrate was concentrated. The residue was flash chromatographed,eluting with 2:1 to 1:1-hexane:ethyl acetate. The appropriate fractionswere collected and evaporated to yield 5.54 g (64%) oferythro-N-[1,3-diacetyloxy-1-(6-hexadecynyl-2-pyridinyl)-2-propanyl]acetamide.

A mixture oferythro-N-[1,3-diacetyloxy-1-(6-hexadecynyl-2-pyridinyl-2-propanyl]acetamide(5.4 g) in ethanol (150 ml) and 5% palladium-on-carbon (0.20 g) wasshaken on a Parr hydrogenator under 35 psi of hydrogen for 2.5 hrs. Thecatalyst was collected and the filtrate was evaporated. The residue waschromatographed to give 4.1 g (75%; 48% overall) of product, mp79°-80.5° C.

Analysis Calculated for C₃₀ H₅₀ N₂ O₅ : 69.46% C 9.72% H 5.40% N Found:69.81% C 9.60% H 5.41% N

EXAMPLE 44erythro-N-[1-(6-Hexadecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide

A mixture oferythro-N-{1-[6-(1-hexadecynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(3.9 g), ethanol (125 ml) and 5% palladium-on-carbon (0.20 g) was shakenon a Parr hydrogenator under 35 psi of hydrogen for 2 hrs. The catalystwas collected and the filtrate was evaporated. The residue wasrecrystallized from ethyl acetate to give 3.6 g (91%) of product, mp98°-101° C.

Analysis: Calculated for C₂₆ H₄₆ N₂ O₃ : 71.85% C 10.67% H 6.44% NFound: 71.92% C 10.75% H 6.52% N

EXAMPLE 45 erythro-2-Amino-(6-hexadecyl-2-pyridinyl)-1,3-propanediol

erythro-N-[1-(6-hexadecyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide(3.0 g), hydrazine hydrate (35 ml), and ethanol (25 ml) were heatedunder reflux, under nitrogen, for 28 hrs. The reaction mixture wascooled, water (40 ml) was added, and the mixture was extracted withchloroform. The combined extracts were washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was chromatographed on silicagel, eluting with 950:50:3-chloroform:methanol:2N ammonium hydroxide.The appropriate fractions were collected and concentrated. The residuewas dissolved in ethyl acetate and the solution was washed withhalf-saturated sodium chloride solution, dried, over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue wasazeotroped with toluene to give 1.37 g (50%) of product, mp 67°-69° C.

Analysis: Calculated for C₂₄ H₄₄ N₂ O₂ : 73.42% C 11.30% H 7.13% NFound: 73.25% C 11.14% H 7.04% N

EXAMPLE 46 Ethylthreo-2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate

A solution of 6-bromo-2-pyridinecarboxaldehyde (30.3 g),acetamidomalonic acid monoethyl ester (34.1 g), and triethylamine (16.6g) in dry tetrahydrofuran (170 ml) was stirred under nitrogen at ambienttemperature overnight. The reaction mixture was concentrated and theresidue was azeotroped three times with ethyl acetate, and thenrecrystallized from ethyl acetate to remove 36.4 g of ethylerythro-2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxyproprionate. Thefiltrate was chromatographed on a silica gel column, eluting with 3:2 to1:1-hexane:ethyl acetate. The appropriate fractions were collected andconcentrated. The residue was recrystallized from ethyl acetate to give1.0 g (2.0%) of product, mp 144°-146° C.

Analysis: Calculated for C₁₂ H₁₅ BrN₂ O₄ : 43.52% C 4.57% H 8.46% NFound: 44.02% C 4.52% H 8.39% N

EXAMPLE 47 6-(1-Undecynyl)pyridine-2-carboxaldehyde

A solution of 6-bromopyridine-2-caboxaldehyde (15.0 g), 1-undecyne (12.9g), triethylamine (24.5 g), bis(triphenylphosphine)palladium(II)chloride(1.1 g, 2%), and copper(I)iodide (0.15 g, 1%) in dry tetrahydrofuran (60ml) was heated under nitrogen at 55° C. for 10 hrs. The reaction mixturewas filtered, the filter cake was washed with ethyl acetate, and thefiltrate was evaporated. The residue was dissolved in ethyl acetate, andthe solution was washed with half-saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was flash chromatographed on silica gel,eluting with 0%-2%-ethyl acetate:hexane. The appropriate fractions werecollected and evaporated to yield 17.5 g (84.0%) of product.

Analysis: Calculated for C₁₇ H₂₃ NO: 79.33% C 9.01% H 5.44% N Found:79.03% C 9.36% H 5.14% N

EXAMPLE 48 Ethylerythro-2-acetamido-3-hydroxy-3-[6-(1-undecynyl)-2-pyridinyl]propionate

A mixture of ethylerythro-2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (20.8g), 1-undecyne (11.5 g), triethylamine (12.7 g),bis(triphenylphosphine)palladium chloride (0.88 g), and cuprous iodide(0.12 g) in dry tetrahydrofuran (100 ml) was heated at 55° C. for 4 hrsunder nitrogen. Additional 1-undecyne (2.9 g), triethylamine (3.2 g),bis(triphenylphosphine)palladium chloride (0.44 g), and cuprous iodide(0.06 g) were added at ambient temperature, and the reaction mixture washeated an additional 5 hrs. The reaction mixture was evaporated and theresidue was dissolved in ethyl acetate. The solution was washed withhalf-saturated sodium chloride solution and the organic phase was flashchromatographed on silica gel, eluting with 3:2 to 1:1-hexane:ethylacetate. The appropriate fractions were collected and evaporated.Recrystallization of the residue from ethyl acetate save 16.0 g (63.4%)of product, mp 92°-93° C.

Analysis: Calculated for C₂₃ H₃₄ N₂ O₄ : 68.63% C 8.51% H 6.96% N Found:68.58% C 8.94% H 6.94% N

EXAMPLE 49erythro-N-{1,3-Dihydroxy-1-[6-(1-undecynyl)-2-pyridinyl]-2-propanyl}acetamide

To ethylerythro-2-acetamido-3-hydroxy-3-[6-(-1-undecynyl)-2-pyridinyl]propionate(17.9 g), in dry tetrahydrofuran (150 ml) was added 2.0M lithiumborohydride/tetrahydrofuran (22 ml) at 0° C. under nitrogen. Thereaction mixture was chilled, stirred at ambient temperature overnight,and 1:1-methanol:water (30 ml) was added followed by of glacial aceticacid (2.8 ml) in 1:1-methanol:water (30 ml) until a pH of 6.4 wasobtained. The solution was stirred at ambient temperature for 1 hr,evaporated, and the residue was azeotroped with methanol. The residuewas slurried with 75% sodium bicarbonate solution (pH 8.5), extractedwith 3:1-chloroform:2-propanol, and concentrated. The residue was flashchromatographed on silica gel, eluting with 0.5%-1% methanol:ethylacetate. The appropriate fractions were collected and concentrated. Theresidue was recrystallized from 1:1-hexane:ethyl acetate to give 12.1 g(75.4%) of product, mp 95°-96.5° C.

Analysis: Calculated for C₂₁ H₃₂ N₂ O₃ : 69.97% C 8.95% H 7.77% N Found:69.84% C 8.87% H 7.71% N

EXAMPLE 50(Z)-erythro-N-{1,3-Dihydroxy-1-{6-(1-octenyl)-2-pyridinyl]-2-propanyl}acetamide

A solution of ethylerythro-2-acetamido-3-[6-(1-octynyl)-2-pyridinyl]-3-hydroxypropionate(9.0 g), in dry tetrahydrofuran (80 ml) and 2.0M lithiumborohydride/tetrahydrofuran (12.5 ml), was stirred under nitrogen at 0°C. The reaction mixture was stirred at ambient temperature overnight,chilled, and 1:1-methanol:water (40 ml) and acetic acid (1.5 ml) wasadded until a pH of 6.8 was obtained. The reaction mixture was stirred 1hr, evaporated, and the residue was azeotroped with methanol. 7.5%Sodium bicarbonate solution was added until a pH of 8.5 was obtained.The mixture was extracted with 3:1-chloroform:-2-propanol andconcentrated. The residue was flash chromatographed on silica gel,eluting with 1% methanol/ethyl acetate to give 7.6 g of material.

Part of the above material (5.0 g) and 8.35 g from a similar experiment,acetic anhydride (25.7 g), triethylamine (38.2 g), and4-dimethylaminopyridine (0.51 g) in tetrahydrofuran (180 ml ) wasstirred at ambient temperature for 3 hrs. The reaction mixture wasevaporated, methanol was added, and the mixture was warmed at 50° C. for20 min, and evaporated. A 7.5% sodium bicarbonate solution was addeduntil a pH of 8.5 was obtained and the mixture was extracted withchloroform. The extract was dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was flashchromatographed, eluting with 2:1-hexane:ethyl acetate. The appropriatefractions were collected and concentrated to yield 1.1 g of(Z)-erythro-N-{1,3-diacetyloxy-1[6-(1-octenyl)-2-pyridinyl]-2-propanyl}acetamide.

A solution of(Z)-erythro-N-{1,3-diacetyloxy-1-[6-(1-octenyl)-2-pyridinyl]-2-propanyl}acetamide(1.1 g), potassium carbonate (0.44 g) in methanol (18 ml) was stirredfor 1 hr. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was chromatographed on silica gel, elutingwith 0.5% methanol/ethyl acetate. The appropriate fractions werecollected and concentrated to give 0.5 g (3.7% overall) of product.

Analysis: Calculated for C₁₈ H₂₈ N₂ O₃ : 67.47% C 8.81% H 8.74% N Found:67.60% C 8.96% H 8.72% N

EXAMPLE 51erythro-N-[1,3-Diacetyloxy-1-(6-octyl-2-pyridinyl)2-propanyl]acetamide

A solution oferythro-N-{1,3-dihydroxy-1-{[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide(13.4 g), acetic anhydride (25.7 g), triethylamine (38.2 g), and4-dimethylaminopyridine (0.51 g) in tetrahydrofuran (180 ml) was stirredat ambient temperature for 3 hrs. The reaction mixture was evaporated,methanol was added to the residue, and the solution was warmed at 50° C.for 20 min and evaporated. A solution of 7.5% sodium bicarbonatesolution was added until a pH of 8.5 was obtained, and the mixture wasextracted with chloroform. The extract was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was flash chromatographed, eluting with 2:1 to 1:1-hexane:ethylacetate. The appropriate fractions were collected and evaporated toyield 9.17 g oferythro-N-[1,3-diacetyloxy-1-(6-octynyl-2-pyridinyl)-2-propanyl]acetamide.

A portion oferythro-N-[1,3-diacetyloxy-1-(6-octynyl-2-pyridinyl)-2-propanyl]acetamide(7.5 g) in ethanol (200 ml) and 5% palladium-on-carbon (0.25 g) wasshaken on a Parr hydrogenator at 40 psi of hydrogen. After 1.5 hrs, thecatalyst was collected and the filtrate was evaporated. The residue waschromatographed to give 6.0 g (78.5%, 43% overall) of product, mp53°-56° C.

Analysis: Calculated for C₂₂ H₃₄ N₂ O₅ : 65.00% C 8.43% H 6.89% N Found:65.07% C 8.32% H 6.88% N

EXAMPLE 52erythro-N-[1,3-Dihydroxy-1-(6-octyl-2-pyridinyl)-2-propanyl]acetamide

A solution oferythro-N-[1,3-diacetyloxy-1-(6-octyl-2-pyridinyl-2-propanyl]acetamide(5.2 g), and potassium carbonate (0.88 g) in methanol (75 ml) wasstirred for 1 hr. The precipitate was collected, and the filtrate wasevaporated. 7.5% Sodium bicarbonate solution and 1N hydrochloric acidwas added until a pH of 8.5 was obtained. The mixture was extracted with3:1-chloroform:2-propanol. The extract was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was evaporated.Recrystallization of the residue from ethyl acetate gave 3.1 g (75.6%)of product, mp 85°-86.5° C.

Analysis: Calculated for C₁₈ H₃₀ N₂ O₃ : 67.05% 9.38% H 8.69% N Found:66.98% C 9.74% H 8.65% N

EXAMPLE 53 erythro-2-Amino-1-(6-octyl-2-pyridinyl)1,3-propanediol

A solution oferythro-N-[1,3-dihydroxy-1-(6-octyl-2-pyridinyl)-2-propanyl]acetamide.(3.8 g), hydrazine hydrate (35 ml), and ethanol (25 ml) was heated underreflux, under nitrogen, for 26 hrs. The reaction mixture was cooled,water (50 ml) was added, and the mixture was extracted with chloroform.The extract was washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. The residue was chromatographed on silica gel, eluting with950:50:3-chloroform:methanol:2N ammonium hydroxide. The appropriatefractions were collected and evaporated. The residue was dissolved inethyl acetate and the solution was washed with half-saturated sodiumchloride solution dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was azeotroped with toluene togive 2.47 g (75%) of product mp 38°-40° C.

Analysis: Calculated for C₁₆ H₂₈ N₂ O₂ 0.1H₂ O: 68.10% C 10.07% H 9.93%N Found 67.88% C 10.18% H 9.74% N

EXAMPLE 54 threo-2-Amino-1-(6-octyl-2-pyridinyl)-1,3-propanediol

A mixture of erythro-andthreo-N-{1,3-dihydroxy-1-[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide(13.4 g), acetic anhydride (25.7 g), triethylamine (38.2 g), and4-dimethylaminopyridine (0.5 g) in tetrahydrofuran (180 ml) was stirredat ambient temperature for 3 hrs. The reaction mixture was evaporated,the residue was warmed with methanol (80 ml) for 20 min, and the mixturewas evaporated. 7.5% Sodium bicarbonate solution was added to a pH of8.5, and the solution extracted with chloroform. The extracts weredried, filtered, and the filtrate was evaporated. The residue was flashchromatographed. The appropriate fractions collected and evaporated toyield 2.4 g (14%) ofthreo-N-{1,3-diacetyloxy-1-[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide.

threo-N-{1,3-Diacetyloxy-1-[6-(1-octynyl)-2-pyridinyl]-2-propanyl}acetamide(2.4 g) in ethanol (75 ml) containing 0.12 g of 5% palladium-on-carbonwas shaken on a Parr hydrogenator at 40 psi of hydrogen. After 3 hrs,the reaction mixture was filtered, and the filtrate was evaporated. Theresidue was flash chromatographed. The appropriate fractions werecollected and evaporated to give 2.2 g (92%) ofthreo-N-[1,3-diacetyloxy-1-(6-octyl-2-pyridinyl)-2-propanyl]acetamide.

A solution ofthreo-N-{1,3-diacetyloxy-1-[6-(1-octyl)-2-pyridinyl]-2-propanyl}acetamide(2.17 g) was stirred with potassium carbonate (70 mg), and methanol (25ml) was stirred for 1 hr at ambient temperature, filtered, and thefiltrate was evaporated. Water was added, the pH was adjusted to 8.5,and the mixture was extracted with 3:1-chloroform:i-2-propanol. Theextract was concentrated to give 1.6 g (94%) ofthreo-N-[1,3-diacetyloxy-1-(6-octyl-2-pyridinyl)-2-propanyl]acetamide,mp 71.5°-74° C.

A solution ofthreo-N-[1,3-diacetyloxy-1-(6-octyl-2-pyridinyl)-2-propanyl]acetamide(1.6 g), hydrazine hydrate (15 ml), and ethanol (15 ml) was heatedwinder reflux, under nitrogen for 23 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. The residue was chromatographed on silica gel, eluting with960:40:3-chloroform:methanol:2N ammonium hydroxide. The appropriatefractions were collected and evaporated to give 0.78 g (56.5%, 7.0%overall) of product, mp 74°-77° C.

Analysis: Calculated for C₁₆ H₂₈ N₂ O₂ : 68.53% C 10.06% H 9.99% NFound: 68.48% C 10.15% H 9.96% N

EXAMPLE 55 erythro-2-Amino-1-(6-hexyl-2-pyridinyl)-1,3-propanediol

A solution oferythro-2-[1-(6-hexyl-2-pyridinyl)-1,3-dihydroxy-2-propanyl]acetamide(3.6 g), hydrazine hydrate (35 ml) and ethanol (25 ml) was heated underreflux, under nitrogen for 29 hrs. The reaction mixture was cooled,water (50 ml) was added, and the mixture was extracted with ethylacetate. The extract was washed with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, filtered and the filtrate wasevaporated. The residue was chromatographed on silica gel, eluting with950:50:3-chloroform:methanol:2N ammonium hydroxide. The appropriatefractions were collected and evaporated. The residue was dissolved inethyl acetate (80 ml), and the solution was washed with half-saturatedsodium chloride solution, dried, filtered, and the filtrate wasevaporated to give 2.02 g, (66%) of product.

Analysis: Calculated for C₁₄ H₂₄ N₂ O₂ : 66.63% C 9.59% H 11.10% NFound: 65.91% C 9.42% H 10.82% N

EXAMPLE 56 6-(7-Phenyl-1-heptynyl)pyridine-2-carboxaldehyde

A solution of 6-bromopyridine-2-caboxaldehyde (30.0 g),7-phenyl-1-heptyne (26.8 g), triethylamine (48.9 g),bis(triphenylphosphine)palladium(II)chloride (2.3 g, 2%), andcopper(I)iodide (0.31 g, 1%) in dry tetrahydrofuran (100 ml) was heatedunder nitrogen at 55° C. for 70 hrs. The reaction mixture was cooled toambient temperature, filtered, and the filtrate was washed with ethylacetate. The filtrate was evaporated. The residue was dissolved in ethylacetate, the solution washed with half-saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and the filtrate wasconcentrated. The residue was flash chromatographed on silica gel,eluting with 0.5% to 2%-ethyl acetate:hexane. The appropriate fractionswere collected and concentrated to yield 29.5 g of the product.

Analysis: Calculated for C₁₉ H₁₉ NO: 82.28% C 6.90% H 5.05% N Found:82.00% C 6.94% H 5.02% N

EXAMPLE 57 Ethylerythro-2-acetamido-3-hydroxy-3-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]propionate

A solution of 6-(7-phenyl-1-heptynyl)pyridine-2-carboxaldehyde (26.5 g),acetamidomalonic acid monoethyl ester (19.2 g), triethylamine (14.6 ml)in dry tetrahydrofuran (125 ml) was stirred at ambient temperature for 3days, under nitrogen. The reaction mixture was evaporated, the residuewas dissolved in ethyl acetate and the solution was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and evaporated. The residue was chromatographed on asilica gel column, eluting with 1:1-hexane:ethyl acetate to give 32.9 g(82.0%) of a mixture of erythro- and threo-isomers. The mixture wasrecrystallized from 1:1-hexane:ethyl acetate to give 4.7 g (11.5%) ofproduct, mp 79.0°-81° C.

Analysis: Calculated for C₂₅ H₃₀ N₂ O₄ : 71.07% C 7.16% H 6.63% N Found:71.27% C 6.89% H 6.63% N

EXAMPLE 58erythro-N-{1,3-Dihydroxy-1-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-3-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]propionate(23.4 g) in dry tetrahydrofuran (200 ml) was added 2.0M lithiumborohydride/tetrahydrofuran (22 ml) at 0° C. under nitrogen. Thereaction mixture was stirred at ambient temperature overnight, chilled,and 1:1-methanol:water (50 ml) was added followed by glacial acetic acid(2.5 ml) in 1:1-methanol:water (30 ml) until a pH of 6.4 was obtained.The solution was stirred at ambient temperature for 1 hr, evaporated,and the residue was azeotroped with methanol. The residue was slurriedwith sodium bicarbonate (40 ml) (pH 8.5), saturated sodium chloridesolution (40 ml) was added, and the mixture was extracted with3:1-chloroform:2-propanol. The extracts were concentrated. The residuewas flash chromatographed on silica gel, eluting with 0.5% to 5%methanol:ethyl acetate. The appropriate fractions were collected andevaporated. Recrystallization of the residue from 1:1-hexane:ethylacetate gave 2.64 g (34%) of product, mp 83°-85° C.

Analysis: Calculated for C₂₃ H₂₈ N₂ O₃ : 72.61% C 7.42% H 7.36% N Found:72.76% C 7.66% H 7.31% N

EXAMPLE 59 Ethylerythro-2-acetamido-3-hydroxy-3-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]propionate

A mixture of ethylerythro-2-acetamido-3-(6-bromo-2-pyridinyl)-3-hydroxypropionate (23.2g), 5-phenyl-1-pentyne (12.1 g), triethylamine (10.6 g),bis(triphenylphosphine)palladium chloride (0.98 g), and cuprous iodide(0.13 g) in dry tetrahydrofuran (100 ml) was heated at 55° C. for 1.5hrs under nitrogen. Additional 5-phenyl-1-pentyne (6.1 g), triethylamine(7.1 g), bis(triphenylphosphine)palladium chloride (0.49 g), and cuprousiodide (0.07 g) were added, and the reaction mixture was heatedovernight. The reaction mixture was filtered and the filtrate wasevaporated. The residue was redissolved in ethyl acetate, washed withhalf-saturated sodium chloride solution, and flash chromatographed onsilica gel, eluting with 1:1-hexane:ethyl acetate. The appropriatefractions were collected. The residue was rechromatographed, elutingwith 1%-methanol:chloroform to give 14.2 g (51.6%) of product.

Analysis: Calculated for C₂₃ H₂₆ N₂ O₄ : 70.03% C 6.64% H 7.10% N Found:69.30% C 6.75% H 6.94% N

EXAMPLE 60erythro-N-{1,3-Dihydroxy-1-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-3-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]propionate(12.3 g) in dry tetrahydrofuran (100 ml) was added 2.0M lithiumborohydride/tetrahydrofuran (15.5 ml) at 0° C., under nitrogen. Thereaction mixture was stirred at ambient temperature overnight, chilled,and 1:1-methanol:water (45 ml) and glacial acetic acid (1.8 ml) wereadded until a pH of 6.5 was obtained. The mixture was stirred at ambienttemperature for 80 min. The reaction mixture was evaporated, the residuewas azeotroped with methanol and slurried with 7.5% sodium bicarbonatesolution (25 ml) (pH 8.5). The mixture was extracted with3:1-chloroform:2-propanol, filtered, and the filtrate was concentrated.The residue was flash chromatographed on silica gel, eluting with 0.5%to 1%-methanol:ethyl acetate. The appropriate fractions were collectedand concentrated to give 6.0 g (54.6%) of product, mp 91°-95° C.

Analysis: Calculated for C₁₂ H₂₄ N₂ O₃ : 71.57% C 6.86% H 7.95% N Found:71.48% C 6.75% H 7.92% N

EXAMPLE 61erythro-N-{1,3-Dihydroxy-1-[6-(5-phenylpentyl)-2-pyridinyl]-2-propanyl}acetamideHydrate

erythro-N-{1,3-Dihydroxy-1-[6-(5-phenyl-1-pentynyl-2-pyridinyl]-2-propanyl}acetamide(5.45 g) in ethanol (150 ml)containing 5% palladium-on-carbon (0.20 g)was shaken on a Parr hydrogenator at 40 psi of hydrogen. After 1.5 hrs,the catalyst was collected. The filtrate was evaporated, and the residuewas chromatographed on silica gel, eluting with 0.5%-1% methanol acetateto give 2.8 g (50%) of product.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₃.H₂ O: 67.36% C 8.07% H 7.48% NFound: 67.95% C 8.02% H 7.53% N

EXAMPLE 62erythro-2-Amino-1-[6-(5-phenylpentyl)-2-pyridinyl]-1,3-propanediolHemihydrate

A solution oferythro-N-{1,3-dihydroxy-1-[6-(5-phenylpentyl)-2-pyridinyl]-2-propanyl}acetamide(3.5 g), hydrazine hydrate (32 ml), and ethanol (25 ml) was heated underreflux, under nitrogen, for 26 hrs. The reaction mixture was cooled,water (40 ml) was added, and the mixture was extracted with chloroform.The extracts were washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. A mixture of the residue and 0.25 g from a similarexperiment was chromatographed on silica gel, eluting with 970:30:2 to950:50:3-chloroform:methanol:2N ammonium hydroxide. The appropriatefractions were collected and evaporated. The residue was dissolved inchloroform (100 ml), and the solution was washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was dried at 70° C. under highvacuum to give 2.23 g (64%) of product.

Analysis: Calculated for C₁₉ H₂₆ N₂ O₂.0.5H₂ O: 70.56% C 8.41% H 8.66% NFound: 70.77% C 8.23% H 8.62% N

EXAMPLE 63erythro-N-{1,3-Dihydroxy-1-[3-(1-undecynyl)phenyl]-2-propanyl}acetamide

To ethylerythro-2-acetamido-3-hydroxy-3-[3-(1-undecynyl)phenyl]propionate (7.3g) in dry tetrahydrofuran (75 ml) was added 2.0M lithiumborohydride/tetrahydrofuran (11.4 ml) at 0° C., under nitrogen. Thereaction mixture was chilled, stirred at ambient temperature overnight,and a mixture of glacial acetic acid (1.3 ml), methanol (25 ml) andwater (25 ml) was added dropwise to a final pH of 6. The solution wasconcentrated and the residue was extracted with ethyl acetate. Theextracts were dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. Trituration of the residue with2:3-ether:hexane and recrystallization of the residue from ethyl acetategave 1.9 g (29%) of product, mp 99°-101° C.

Analysis: Calculated for C₂₂ H₃₃ NO₃ : 73.50% C 9.25% H 3.90% N Found:73.56% C 9.05% H 3.93% N

EXAMPLE 64 erythro-N-{1-[3-(1-Dodecynyl)phenyl]-1,3dihydroxy-2-propanyl}acetamide

To ethylerythro-2-acetamido-3-[3-(1-dodecynyl)phenyl]-3-hydroxypropionate (24.0g) in tetrahydrofuran (220 ml) was added 2N lithiumborohydride/tetrahydrofuran (29 ml) at 2° C., under nitrogen. Thereaction mixture was chilled, stirred at ambient temperature for 2.5hrs. and 1:1-methanol:water (100 ml) and glacial acetic acid (3.3 ml)was added slowly until a pH of 6.5 was obtained. The solution wasstirred at ambient temperature for 0.5 hr, evaporated, and the residuewas azeotroped with methanol. The residue was slurried with 7.5% sodiumbicarbonate solution (50 ml) (pH 8.5),and the mixture was extracted with3:1-chloroform:propanol. The extract was concentrated. The residue wasflash chromatographed on silica gel, eluting with ethyl acetate. Theappropriate fractions were collected and evaporated. Recrystallizationof the residue from ethyl acetate gave 9.13 g (42.4%) of product, mp93°-95° C.

Analysis: Calculated for C₂₃ H₃₅ NO₃ : 73.96% C 9.44% H 3.75% N Found:73.66% C 9.14% H 3.69% N

EXAMPLE 65erythro-N-[1-(3-Dodecylphenyl)-1,3-dihydroxy-2-propanyl]acetamide

erythro-N-{1-(3-Dodecynyl)phenyl]-1,3-dihydroxy-2-propanyl}acetamide(4.4 g) in ethanol (100 ml) containing 5% palladium-on-carbon (0.02 g)was shaken on a Parr hydrogenator at 35 psi of hydrogen for 2.5 hrs. Thecatalyst was collected, the solvent evaporated, and the residue wasrecrystallized from ethyl acetate to give 4.1 g (90.6%) of product, mp101°-104° C.

Analysis: Calculated for C₂₃ H₃₉ NO₃ : 73.17% C 10.41% H 3.71% N Found:72.82% C 10.36% H 3.54% N

EXAMPLE 66 erythro-2-Amino-1-(3-dodecylphenyl)-1,3-propanediol

erythro-N-[1-(3-Dodecylphenyl)-1,3-dihydroxy-2-propanyl]acetamide (2.9g), hydrazine hydrate (25 ml), and ethanol (25 ml) were heated underreflux, under nitrogen for 22 hrs. The reaction mixture was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with950:50:3-chloroform:methanol:2N ammonium hydroxide. The appropriatefractions were collected and evaporated. The residue was dissolved inethyl acetate (75 ml), and the solution was washed with half-saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,evaporated, and the residue was azeotroped with toluene to give 1.35 g(52%) of product, mp 36°-40° C.

Analysis: Calculated for C₂₁ H₃₇ NO₂ : 75.17% C 11.12% H 4.17% N Found:75.14% C 11.18% H 4.12% N

EXAMPLE 67 erythroN-[1-[5-(1-Dodecyl)-2-thienyl]-1,3-diacetoxy-2-propyl]acetamide

A solution of erythroN-[1-[5-(1-dodecyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide (12.0g), acetic anhydride (19.2 g), triethylamine (28.4 g),anddimethylaminopyridine (0.4 g) in dry tetrahydrofuran (150 ml) wasstirred at ambient temperature for 3 hrs. The reaction mixture wasevaporated and the residue was dissolved in chloroform. The solution waswashed with water, dried, filtered, and the filtrate was evaporated. Theresidue was dried to give 13.6 g (93.5%) of product, mp 105°-107° C.

Analysis: Calculated for C₂₅ H₄₁ NO₅ S: 64.21% C 8.84% H 2.99% N Found:64.33% C 8.92% H 3.02% N

EXAMPLE 68 Ethylerythro-2-acetamide-3-[5-(1-nonynyl)-2-thienyl]-3-hydroxypropionate

A slurry of 5-nonynyl-2-thiophenecarboxaldehyde (40.0 g),acetamidomalonic acid monoethyl ester (32.3 g) and dry tetrahydrofuran(150 ml) was degassed and cooled to 0° C. Triethylamine (18.2 g) wasadded, the solution degassed, and the reaction mixture was stirred atroom temperature under nitrogen for four days, Acetamidomalonic acidmonoethyl ester (32.3 g) and triethylamine (18.2 g) were added, and thereaction mixture was stirred at room temperature under nitrogen for anadditional four days. The reaction mixture was evaporated and theresidue dried under vacuum. The residue was flash chromatographed(silica; 1:1-ethyl acetate:hexane). The appropriate fractions werecollected and evaporated. The residue was crystallized from ether, thenrecrystallized twice from ethyl acetate to give 40.2 g (62%) of product,mp 104°-106° C.

Analysis: Calculated for C₂₀ H₂₉ NO₄ S: 63.30% C 7.70% H 3.69% N Found:63.30% C 7.64% H 3.71% N

EXAMPLE 69erythro-N-[1-[5-(1-Nonynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[5-(1-nonynyl)-2-thienyl]-3-hydroxypropionate(40.0 g) in dry tetrahydrofuran (150 ml) was stirred at 0° C. undernitrogen as lithium borohydride (2.0M in tetrahydrofuran, 68.5 ml) wasadded dropwise. The reaction mixture was stirred under a nitrogenatmosphere overnight, warming to room temperature. A solution of50:50:8-methanol:water:acetic acid (108 ml) was added, with cooling inan ice-bath. The solution was neutralized with glacial acetic acid andevaporated. The residue was diluted with water and extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed (silica; 2-4%-methanol-ethyl acetate). Theappropriate fractions were collected and evaporated. The residue wasrecrystallized twice from ethyl acetate to give 29.9 g (84%) of product,mp 81°-83° C.

Analysis: Calculated for C₁₈ H₂₇ NO₃ S: 64.06% C 8.06% H 4.15% N Found:64.04% C 8.17% H 4.16% N

EXAMPLE 70 erythro-2-Amino-1-[5-(1-nonynyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[1-[5-(nonynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(16.4 g), 2N sodium hydroxide solution (150 ml), and 95% ethanol (75 ml)was stirred at 70° C. overnight. The reaction mixture was cooled to roomtemperature and acidified with glacial acetic acid. The solution wasdiluted with water (200 ml), basified with sodium bicarbonate solutionand chilled. The precipitate was collected, and the filtrate wasextracted with 4:1-chloroform:2-propanol. The combined organic extractswere dried over anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was combined with the precipitate and flashchromatographed (silica, 90:9:1-dichloromethane:methanol:ammoniumhydroxide) to give 11.8 g (82%) of product. A portion of product wascrystallized from ether to give the analytical sample, mp 64°-67° C.

Analysis: Calculated for C₁₆ H₂₅ NO₂ S: 65.05% C 8.53% H 4.74% N Found:65.22% C 8.56% H 4.76% N

EXAMPLE 71erythro-N-[1-[5-(1-Nonyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A mixture oferythro-N-[1-[5-(1-nonynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(8.00 g), 5% palladium-on-carbon (800 mg), and absolute ethanol (500 ml)was shaken under 50 psi of hydrogen overnight. The catalyst was filteredthrough a bed of celite, and the filtrate was washed with ethanol. Thefiltrate was evaporated, and the residue was recrystallized twice fromethyl acetate to give 7.0 g (86%) of product, mp 98°-100° C.

Analysis: Calculated for C₁₈ H₃₁ NO₃ S: 63.31% C 9.15% H 4.10% N Found:63.03% C 9.14% H 4.01% N

EXAMPLE 72 5-(6-Phenyl-1-hexynyl)-2-thiophenecarboxaldehyde

A solution of 6-phenyl-1-hexyne (30.6 g),5-bromo-2-thiophenecarboxaldehyde (37.0), and triethylamine (58.7 g) indry tetrahydrofuran (75 ml) was degassed and stirred at room temperatureunder a nitrogen atmosphere. Two mole percent ofbis(triphenylphosphine)palladium(II)chloride (2.7 g) followed by onemole percent of copper(I)iodide (0.4 g) was added, The mixture wasdegassed and stirred at room temperature under nitrogen overnight. Theprecipitate was filtered and washed with ethyl acetate. The filtrate wasevaporated, and the residue was distilled to give 47.0 g (91%) ofproduct. A two gram-portion of product was flash chromatographed(silica, 1:1-toluene:hexane). The appropriate fractions were collectedand evaporated. The residue was distilled in a kugelruhr oven (170°C./0.07 mm mercury) to give the analytical sample, as an oil.

Analysis: Calculated for C₁₇ H₁₆ OS: 76.08% C 6.01% H Found: 75.54% C6.04% H

EXAMPLE 73erythro-N-[1-[5-(6-Phenyl-1-hexynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[5-(6-phenyl-1-hexynyl)-2-thienyl]-3-hydroxypropionate(41.6 g) in dry tetrahydrofuran (150 ml) was stirred at 0° C., undernitrogen, as a solution of lithium borohydride (2.0M in tetrahydrofuran,66 ml) was added dropwise. The reaction mixture was warmed to roomtemperature and stirred under a nitrogen atmosphere for four hrs. Asolution of 50:50:8 methanol:water:acetic acid (108 ml) was added withcooling in an ice-bath. Glacial acetic acid was added, and the solutionwas evaporated. Water was added to the residue, and the solution wasextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed (silica; 90:9:1dichloromethane:methanol:2N ammonium hydroxide). The appropriatefractions were collected and evaporated. Recrystallization of theresidue from ethyl acetate gave 31.5 g (84%) of product, mp 131°-133° C.

Analysis: Calculated for C₂₁ H₂₅ NO₃ S: 67.90% C 6.78% H 3,77% N Found:67.54% C 6.88% H 3.71% N

EXAMPLE 74erythro-2-Amino-1-[5-(6-phenyl-1-hexynyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[1-[5-(6-phenyl-1-hexynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(10.0 g), 1N sodium hydroxide solution (125 ml) and 95% ethanol (75 ml)was stirred at 65° C. overnight. The reaction mixture was evaporated,and the residue was neutralized with glacial acetic acid. The solutionwas diluted with water (200 ml) and extracted with4:1-chloroform:2-propanol. The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed (silica;90:9:1-dichloromethane:methanol:2N ammonium hydroxide). The appropriatefractions were collected and evaporated to give 7.8 g (88%) of product.A portion was crystallized from ethyl acetate-hexane to give theanalytical sample, mp 130°-140° C. (dec).

Analysis: Calculated for C₁₉ H₂₃ NO₂ S: 69.27% C 7.04% H 4.25% N Found:69.29% C 7.14% H 4.26% N

EXAMPLE 75 4-(1-Dodecynyl)-2-thiophenecarboxaldehyde

A solution of 1-dodecyne (23.9 g), 5-bromo-2-thiophenecarboxaldehyde(25.0 g) and triethylamine (39.7 g) in dry tetrahydrofuran (75 ml) wasdegassed and stirred at room temperature under a nitrogen atmosphere.Two mole percent of bis(triphenylphosphine)palladium(II)chloride (1.8 g)followed by one mole percent of copper(I)iodide (0.25 g) was added. Themixture was degassed and stirred at room temperature under nitrogen forthree days. The precipitate was filtered, and the filter cake was washedwith ethyl acetate. The filtrate was evaporated, and the residue wasflash chromatographed (silica, 7:3-Hexane:dichloromethane). Theappropriate fractions were collected and evaporated. The residue wasdried at 50° C. under vacuum for three hrs to give 35.5 g (98%) ofproduct.

Analysis: Calculate for C₁₇ H₂₄ OS: 73.86% C 8.75% H Found: 73.79% C9.08% H

EXAMPLE 76 Ethylerythro-2-acetamide-3-[4-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate

A slurry of 4-(1-dodecynyl)-2-thiophenecarboxaldehyde (21.4 g),acetamidomalonic acid monoethyl ester (14.6 g), and dry tetrahydrofuran(100 ml) was degassed and cooled to 0° C. Triethylamine (8.23 g) wasadded, the solution degassed, and the reaction stirred at roomtemperature under nitrogen for five days. Additional acetamidomalonicacid monoethyl ester (14.6 g) and triethylamine (8.23 g) were added, andthe reaction was stirred at room temperature under nitrogen for fivedays. The reaction mixture was evaporated, the residue dried undervacuum, and flash chromatographed (silica, 3:2-hexane:ethyl acetate).The appropriate fractions were collected and evaporated. The residue wasrecrystallized from ethyl acetate-hexane to 23.3 g (71%) of product, mp79°-81° C.

Analysis: Calculated for C₂₃ H₃₅ NO₄ S: 65.53% C 8.37% H 3.32% N Found:65.63% C 7.96% H 3.34% N

EXAMPLE 77 erythro-2-Amino-1-[4-(1-dodecyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[1-[4-(dodecyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(6.35 g), 2N sodium hydroxide solution (100 ml) and 95% ethanol (50 ml)was stirred at 65° C. overnight. The reaction mixture was cooled to roomtemperature and neutralized with glacial acetic acid, The solution wasdiluted with water (200 ml) and chilled. The precipitate was collected,and the filtrate was extracted with chloroform. The combined organicextracts were dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated. The residue was combined with the precipitateand flash chromatographed (silica, 90:9:1-dichloromethane:methanol:2Nammonium hydroxide). The appropriate fractions were collected andevaporated. The residue was recrystallized from ethyl acetate to give4.1 g (73%) of product, mp 99°-100° C.

Analysis: Calculated for C₁₉ H₃₅ NO₂ S: 66.81% C 10.33% H 4.10% N Found:66.70% C 10.40% H 4.11% N

EXAMPLE 78 Ethylerythro-2-acetamido-3-[5-(6-phenyl-1-hexynyl)-2-thienyl]-3-hydroxypropionate

A slurry of 6-phenyl-1-hexynyl-2-thiophenecarboxaldehyde (45.0 g),acetamidomalonic acid monoethyl ester (31.7 g), and dry tetrahydrofuran(150 ml) was degassed and cooled to 0° C. Triethylamine (17.9 g) wasadded, the solution degassed, and the reaction mixture stirred at roomtemperature under nitrogen for two days. Additional acetamidomalonicacid monoethyl ester (31.7 g) and triethylamine (17.9 g) were added, andthe reaction mixture was stirred at room temperature under nitrogen foran additional two days. The mixture was evaporated, the residue driedunder vacuum, and flash chromatographed (silica, 1:1-ethylacetate:hexane). The appropriate fractions were collected andevaporated. The residue was recrystallized from ethyl acetate-hexane togive 48.1 g (69%) of product, mp 90°-92° C.

Analysis: Calculated for C₂₃ H₂₇ NO₄ S: 66.80% C 6.58% H 3.39% N Found:66.48% C 6.59% H 3.33% N

EXAMPLE 79erythro-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol]acetate

A solution oferythro-N-[1-[4-(dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(4.30 g), 2N sodium hydroxide solution (100 ml), and 95% ethanol (50 ml)was stirred at 65° C. overnight. The reaction mixture was cooled to roomtemperature and acidified with glacial acetic acid. The solution wasdiluted with water (200 ml) and chilled in the refrigerator. Theprecipitate was collected and the filtrate extracted with chloroform.The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was combined withthe precipitate and previously prepared material, and recrystallizedtwice from ethyl acetate to give 4.0 g (55%) of product, mp 120°-122° C.

Analysis: Calculated for C₂₁ H₃₅ NO₂ S: 63.44% C 8.87% H 3.52% N Found:63.32% C 8.71% H 3.50% N

EXAMPLE 80erythro-N-[1-[4-(1-Dodecyl)-2-thienyl]1,3-dihydroxy-2-propyl]acetamide

A mixture oferythro-N-[1-[4-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(8.00 g), 5% palladium-on-carbon (800 mg), and absolute ethanol (500 ml)was shaken under 50 psi of hydrogen overnight. The reaction mixture wasfiltered through a bed of celite, and the filter cake was washed withethanol. The solvent was evaporated and the residue recrystallized twicefrom ethyl acetate to give 7.0 g (87%) of product, mp 92°-94° C.

Analysis: Calculated for C₂₁ H₃₇ NO₃ S: 65.75% C 9.72% H 3.65% N Found:65.72% C 9.82% H 3.63% N

EXAMPLE 81erythro-2-Amino-1-[3-(1-dodecyl)-5-isoxazolyl]-1,3-propanediol

A solution oferythro-N-[1-[3-(1-dodecyl)-5-isoxazolyl]-1,3-dihydroxy-2-propyl]acetamide(4.0 g), degassed 2N sodium hydroxide solution (100 ml), and 95% ethanol(50 ml) was stirred at 60° C. for 3 hrs. The reaction mixture wasconcentrated, the residue diluted with sodium bicarbonate solution, andextracted with 4:1-chloroform-2-propanol. The combined organic extractswere dried over anhydrous magnesium sulfate, filtered, and the filtratewas evaporated. The residue was recrystallized from ethylacetate-hexane.The precipitate was flash chromatographed (silica,90:1-dichloromethane:methanol). The appropriate fractions were collectedand evaporated. The residue was recrystallized from ethyl acetate-hexaneto give 2.3 g (65%) of product, mp 88°-90° C.

Analysis: Calculated for C₁₈ H₃₄ N₂ O₃ : 66.22% C 10.50% H 8.58% NFound: 65.55% C 10.44% H 8.51% N

EXAMPLE 82 3-(1-Decyl)-5-isoxazolemethanol

To a solution of 1-nitroundecane (38.0 g) and O-trimethylsilylpropynol(24.1 g) in dry benzene (300 ml) was added dropwise a solution offreshly distilled phenylisocyanate (44.9 g) and triethylamine (22.4 g)in dry benzene (50 ml) at 40° C., with stirring. The reaction mixturewas heated at 60° C. for 3 hrs, cooled, and filtered. To the filtratewas added 1.0M tetrabutylammonium fluoride (40 ml). After 30 mins, thesolution was evaporated, and the residue was flash chromatographed(silica gel, 1% methanol-dichloromethane) to give 15.5 g (34%) ofproduct, mp 55°-56° C.

Analysis: Calculated for C₁₄ H₂₅ NO₂ : 70.25% C 10.53% H 5.85% N Found:70.44% C 10.42% H 5.92% N

EXAMPLE 83 3-(1-Decyl)-5-isoxazolecarboxaldehyde

To a solution of oxalyl chloride (31.7 ml) in dry dichloromethane (100ml) cooled to -60° C., was added a solution of dimethylsulfoxide (9.8ml) in dichloromethane (30 ml) followed by a slurry of3-(1-decyl)-5-isoxazolemethanol (13.8 g) in dry dichloromethane (100ml). The reaction mixture was stirred at -60° C. for 0.5 hr, quenchedwith triethylamine (40 ml), and allowed to warm to ambient temperature.The solution was poured into water (300 ml) and extracted withdichloromethane. The organic phases were washed with dilute citric acid,dried, and evaporated. The residue was flash chromatographed (silica,50:1-dichloromethane:methanol). The appropriate fraction were collectedand evaporated. The residue was recrystallized from ether-hexane to give11.2 g (82%) of product, mp 46°-48° C.

Analysis: Calculated for C₁₄ H₂₃ NO₂ : 70.85% C 9.77% H 5.90% N Found:71.16% C 9.93% H 5.94% N

EXAMPLE 84 Ethylerythro-2-acetamido-3-(3-(1-decyl)-5-isoxazolyl)-3-hydroxypropionate

To a mixture of 3-(decyl)-5-isoxazolecarboxaldehyde (10 g), andacetamidomalonic acid monoethylester (7.9 g) in dry tetrahydrofuran (100ml), cooled to 0° C., was added triethylamine (4.5 g), under nitrogen.The solution was allowed to warm to room temperature and stirred for 16hrs. The solution was evaporated, and the residue was recrystallizedtwice from ethyl acetate-hexane to give 10.3 g (64%) of product, mp83°-85° C.

Analysis: Calculated for C₂₀ H₃₄ N₂ O₅ : 62.80% C 8.96% H 7.32% N Found:62.87% C 9.30% H 7.32% N

EXAMPLE 85 erythro-2-Amino-1-[3-(1-decyl)-5-isoxazolyl]-1,3-propanediol

A solution oferythro-N-[1-[5-(decyl)-3-isoxazolyl]-1,3-dihydroxy-2-propyl]acetamide(9.30 g), degassed 2N sodium hydroxide solution (200 ml), and 95%ethanol (100 ml) was stirred at 80° C. for 6 hrs. The reaction mixturewas concentrated, the residue diluted with sodium bicarbonate solution,and extracted with 4:1-chloroform:2-propanol. The combined organicextracts were dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was flash chromatographed (silica;9:1 dichloromethane:methanol). The appropriate fractions were collectedand evaporated. The residue was recrystallized from ethyl acetate-hexaneto give 6.1 g (75%) of product, mp 88°-90° C.

Analysis: Calculated for C₁₆ H₃₀ N₂ O₃ : 64.40% C 10.13% H 9.39% NFound: 64.37% C 10.25% H 9.42% N

EXAMPLE 86 5-(1-Undecynyl)-2-thiophenecarboxaldehyde

A solution of 1-undecyne (62.7 g), 5-bromo-2-thiophenecarboxaldehyde(75.0 g), and triethylamine (119.2 g) in dry tetrahydrofuran (300 ml)was degassed and stirred at °-5° C., under a nitrogen atmosphere. Twomole percent of bis(triphenylphosphine)palladium(II)chloride (5.51 g)followed by one mole percent of copper(I)iodide (0.75 g) was added andthe mixture was degassed and stirred at room temperature overnight,under nitrogen. The precipitate was filtered and the filter cake waswashed with ethyl acetate. The filtrate was evaporated and the residuepurified by flash chromatography (silica; 5% ethyl acetate-hexane). Theappropriate fractions were collected and evaporated to give 88.1 g (85%)of product as an oil. The oil was dried at 50° C. under high vacuum(approx. 0.01 mm mercury) for four hrs to provide the analytical sample.

Analysis: Calculated for C₁₆ H₂₂ OS: 73.23% C 8.45% H Found: 73.15% C8.50% H

EXAMPLE 87 Ethylerythro-2-acetamido-3-[5-(1-undecynyl)-2-thienyl]-3-hydroxypropionate

A slurry of 5-undecynyl-2-thiophenecarboxaldehyde (86.1 g),acetamidomalonic acid monoethyl ester (62.0 g), and dry tetrahydrofuran(300 ml) was degassed and cooled to 0° C. Triethylamine (34.8 g) wasadded, the solution were degassed, and the reaction mixture was stirredat room temperature for four days, under nitrogen. Acetamidomalonic acidmonoethyl ester (62.0 g) and triethylamine (34.8 g) were added, and thereaction mixture was stirred at room temperature for an additional twodays, under nitrogen. The reaction mixture was evaporated, and theresidue was dried under vacuum. The residue was purified by flashchromatography (silica; 1:1-ethyl acetate-hexane). The appropriatefractions were collected and evaporated, and the residue wasrecrystallized from ethyl acetate to give 86.5 g (65%) of product, mp80°-82° C.

Analysis: Calculated for C₂₂ H₃₃ NO₄ S: 64.83% C 8.16% H 3.44% N Found:64.65% C 8.07% H 3.45% N

EXAMPLE 88erythro-N-[1-[5-(1-Undecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[5-(1-undecynyl)-2-thienyl]-3-hydroxypropionate(86.2 g) in dry tetrahydrofuran (200 ml) was stirred at 0° C., undernitrogen. Lithium borohydride (137.5 ml, 2.0M in tetrahydrofuran) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature, and was stirred for four hrs, under nitrogen. The reactionmixture was cooled in an ice-bath. Methanol:water:acetic acid solution(50 ml:50 ml:10 ml) was added. The solution was neutralized with glacialacetic acid. The mixture was evaporated, and the residue was dilutedwith water (400 ml) and extracted with ethyl acetate. The combinedorganic extracts were dried over anhydrous sodium sulfate, filtered, andthe filtrate was evaporated. The residue was purified by flashchromatography (silica; 7% methanol:dichloromethane). The appropriatefractions were collected and evaporated. Recrystallization of theresidue from ethyl acetate gave 61.2 g (79%) of product, mp 88°-90° C.

Analysis: Calculated for C₂₀ H₃₁ NO₃ S: 65.72% C 8.55% H 3.83% N Found:66.00% C 8.71% H 3.82% N

EXAMPLE 89(4-trans)-N-[2,2-Dimethyl-4-[5-(1-undecynyl)-2-thienyl]-1,3-dioxan-5-yl]acetamide

To a solution oferythro-N-[1-[5-(1-undecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(25 g) in dry acetone (400 ml) was added 2,2-dimethoxypropane (45.3 g)and a catalytic amount of para-toluenesulfonic acid. The solution wasstirred at room temperature for 7 hrs and then evaporated. The residuewas purified by column chromatography (silica gel, 4:1chloroform:ether). The appropriate fractions were collected andconcentrated. Recrystallization from ether-hexane gave 20.9 g (73.8%) ofproduct, mp 88°-89° C.

Analysis: Calculated for C₂₃ H₃₅ NO₃ S: 68.11% C 8.70% H 3.45% N Found:68.26% C 8.83% H 3.39% N

EXAMPLE 90erythro-N-[1-[5-(1-Nonynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]-1,1-dimethylethylcarbamate

To a slurry oferythro-2-amino-1-[5-(1-nonynyl)-2-thienyl]-1,3-propanediol (2.8 g) insaturated sodium bicarbonate solution (50 ml) was added a solution ofdi-tert-butyl dicarbonate (2.24 g) in chloroform (50 ml), over two mins.The mixture was stirred at 60° C. for 45 mins, the layers wereseparated, and the organic layer was dried and evaporated. The residuewas purified by passage through a short pad of silica gel, and thefiltrate was evaporated. The residue was crystallized from ether-hexaneto give 2.9 g (77.6%) of product, mp 73°-75° C.

Analysis: Calculated for C₂₁ H₃₃ NO₄ S: 63.77% C 8.41% H 3.54% N Found:63.65% C 8.31% H 3.50% N

EXAMPLE 91 erythro-2-Amino-1-[5-(1-nonyl)-2-thienyl]-1,3-propanediolAcetate

A solution oferythro-N-[1-[5-(1-nonyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(7.30 g), 2N sodium hydroxide solution (100 ml) and 95% ethanol (75 ml)was stirred at 65° C. overnight. The reaction mixture was concentrated,and the aqueous residue was neutralized with glacial acetic acid. Thesolution was diluted with water (200 ml) and extracted with4:1-chloroform:isopropanol. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was purified by flash chromatography (silica;90:9:1-dichloromethane:methanol:ammonium hydroxide). The appropriatefractions were collected and concentrated. The residue was dissolved inethanol, and excess glacial acetic acid was added. Ether and hexane wereadded. The precipitate was recrystallized from ethyl acetate to give 4.1g (53%) of product, mp 109°-111° C.

Analysis: Calculated for C₁₈ H₃₃ NO₄ S: 60.13% C 9.25% H 3.90% N Found:60.02% C 8.99% H 3.90% N

EXAMPLE 92erythro-2-Dimethylamino-1-[5-(6-phenyl-1-hexynyl)-2-thienyl]-1,3-propanedio

To a mixture oferythro-2-amino-1-[5-(6-phenyl-1-hexynyl)-2-thienyl]-1,3-propanediol(4.0 g), 37% aqueous formaldehyde (9.1 ml), and acetonitrile (50 ml) wasadded sodium cyanoborohydride (2.29 g) in three portions, with stirringat room temperature. After stirring for 30 mins, glacial acetic acid (1ml) was added dropwise, and stirring was continued for 30 mins. Themixture was neutralized with acetic acid and evaporated. 1N Sodiumhydroxide (200 ml) was added to the residue, and the mixture wasextracted with chloroform. The extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed on silica gel, using 10% methanol:dichloromethaneas eluent. The appropriate fractions were collected and evaporated togive 1.3 g (30%) of product, as an oil.

EXAMPLE 93 4-(1-Dodecenyl)-2-thiophenecarboxaldehyde

A solution of 1-dodecyne (50.0 g), tributyltinhydride (109.4 g), andazobisisobutyronitrile (100 mg) was stirred at 95° C. for 3 hrs. Thereaction mixture was cooled to 50° C. and evaporated. The residue wasfiltered through a column of silica, using hexane as the eluent. Theappropriate fractions were collected and evaporated. The residue wasdried under vacuum to give 131.7 g (96.0%) oftri-n-butyl-1-dodecenylstannane.

To a solution of 4-bromo-2-thiophenecarboxaldehyde (35.0),tetrakis(triphenylphosphine)palladium(0) (4.23 g),2,6-di-t-butyl-4-methylphenol (a few milligrams) and dry toluene (150ml) was added tri-n-butyl-1-dodecenylstannane (92.0 g), dropwise at roomtemperature, under nitrogen. The solution was heated under reflux forfour hrs, with stirring. After cooling to room temperature, the solutionwas filtered through a bed of celite, and the filter cake was washedwith ether. The filtrate was evaporated and the residue purified byflash chromatography (silica; 5% ethyl acetate-hexane). The appropriatefractions were collected and concentrated. The residue was distilled ina kugelrohr oven (170° C./0.3 mm mercury) to give 46.7 g (92%) ofproduct, as an oil (ca. 4:1-trans:cis).

Analysis: Calculated for C₁₇ H₂₆ OS: 73.33% C 9.41% H Found: 73.64% C9.62% H

EXAMPLE 94 Ethylerythro-2-acetamido-3-[5-(1-dodecenyl)-2-thienyl]-3-hydroxypropionate

A slurry of 5-dodecenyl-2-thiophenecarboxaldehyde (46.0 g, ca.4:1-trans:cis), acetamidomalonic acid monoethyl ester (31.3 g), and drytetrahydrofuran (300 ml) was degassed and cooled to 0° C. Triethylamine(17.6 g) was added, the solution was degassed, and the reaction mixturewas stirred at room temperature for three days, under nitrogen.Acetamidomalonic acid monoethyl ester (46.0 g) and triethylamine (17.6g) were added, and the reaction mixture was stirred at room temperaturefor an additional three days, under nitrogen. The reaction mixture wasconcentrated, and the residue was dried under vacuum. The residue waswas purified by flash chromatography (silica; 2:3 ethyl acetate-hexane).The appropriate fractions were collected and concentrated. The residuewas recrystallized from diethyl ether to give 36.7 g (53%) of product(ca. 4:1-trans:cis), mp 66°-68° C.

Analysis: Calculated for C₂₃ H₃₇ NO₄ S: 65.21% C 8.80% H 3.31% N Found:65.36% C 8.71% H 3.32% N

EXAMPLE 95erythro-N-{1.3-Diacetyloxy-1-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]-2-propanyl}acetamide

A diastereomeric mixture ofN-{1,3-dihydroxy-1-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]-2-propanyl}acetamide(18.4 g, 6:1-erythro:threo), acetic anhydride (31.9 g), triethylamine(47.5 g), and 4-dimethylaminopyridine (0.64 g) in tetrahydrofuran (200ml) was stirred at room temperature overnight. The reaction mixture wasconcentrated, methanol was added, and the mixture was warmed at 50° C.for 20 mins. The mixture was evaporated, and the residue azeotroped withtoluene. A 7.5% sodium bicarbonate solution was added until pH 8.5, andthe mixture was extracted into chloroform. The extract was dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue and one (8.0 g) from a similar reaction (18.8mmol) were combined and purified by flash chromatography, eluting with1:1-yield hexane:ethyl acetate. The appropriate fractions were collectedand concentrated to yield 5.06 g (16.3% yield) of product, mp 104°-106°C.

Analysis: Calculated for C₂₅ H₂₈ N₂ O₅ : 68.79% C 6.47% H 6.42% N Found:68.69% C 6.47% H 6.36% N

EXAMPLE 96erythro-2-Amino-1-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]-1,3-propanediolHemihydrate

erythro-N-{1,3-Dihydroxy-1-[6-(5-phenyl-1-pentynyl)-2-pyridinyl]-2-propanyl}acetamide(4.4 g), 2N sodium hydroxide solution (100 ml) and ethanol (50 ml) wereheated at 60° C. for 13 hrs, under nitrogen. The reaction mixture wascooled, extracted with chloroform, and the extract was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed twice on silica gel eluting with 950:50:3 to 920:80:5chloroform:methanol:2N ammonium hydroxide. The appropriate fractionswere collected and concentrated. The residue was dissolved in ethylacetate, and the solution was washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated to give 1.13 g (36.5%) of product, as an oil(dried 60° C. under vacuum).

Analysis: Calculated for C₁₉ H₂₂ N₂ O₂ 0.5H₂ O: 71.44% C 7.26% H 8.77% NFound: 71.87% C 7.11% H 8.67% N

EXAMPLE 97erythro-N-[1,3-Dihydroxy-1-(6-undecyl-2-pyridinyl)-2-propanyl]acetamide

A mixture oferythro-N-{1,3-Dihydroxy-1-[6-(1-undecynyl)-2-pyridinyl]-2-propanyl}acetamide(5.4 g) in ethanol (125 ml), and 5% palladium-on-carbon (0.20 g) washydrogenated on a Parr hydrogenator at 40 psi of hydrogen. After 2.5hrs, the catalyst was filtered, and the filtrate was concentrated.Recrystallization of the residue from ethyl acetate gave 4.9 g (88.7%)of product, mp 97°-98.5° C.

Analysis: Calculated for C₂₁ H₃₆ N₂ O₃ : 69.19% C 9.95% H 7.68% N Found:69.19% C 9.91% H 7.64% N

EXAMPLE 98 erythro-2-Amino-1-(6-undecyl-2-pyridinyl)-1,3-propanediol

erythro-N-[1,3-Dihydroxy-1-(6-undecyl-2-pyridinyl)-2-propanyl]acetamide(3.72 g), hydrazine hydrate (32 ml), and ethanol (25 ml) were refluxedfor 24 hrs, under nitrogen. The reaction mixture was cooled, water wasadded, and the mixture was extracted with chloroform. The extract waswashed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was evaporated. Theresidue was chromatographed on silica gel, eluting with 950:50:3chloroform:methanol:2N ammonium hydroxide. The appropriate fractionswere collected and evaporated. The residue was dissolved in chloroform,the solution was washed with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated to give 1.45 g (44%) of product, mp 56°-59° C. (dried at55° C. under vacuum).

Analysis: Calculated for C₁₉ H₃₄ N₂ O₂ : 70.76% C 10.63% H 8.69% NFound: 70.20% C 10.71% H 8.48% N

EXAMPLE 99erythro-2-Amino-1-[6-(1-undecynyl)-2-pyridinyl]-1,3-propanediolHemihydrate

erythro-N-{1,3-Dihydroxy-1-[6-(1-undecynyl)-2-pyridinyl]-2-propanyl}acetamide(5.4 g), 2N sodium hydroxide (53 ml), and ethanol (35 ml) were heated at60° C. for 19 hrs, under nitrogen. The reaction mixture was cooled,extracted with chloroform, and the extract was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. The residue waschromatographed twice on silica gel, eluting with 950:50:3 to 930:70:5chloroform:methanol:2N ammonium hydroxide. The appropriate fractionswere collected and concentrated to give 3.04 g (63.6% yield) of product,as an oil dried at 60° C. under vacuum.

Analysis: Calculated for C₁₉ H₃₀ N₂ O₂ 0.5H₂ O: 69.69% C 9.54% H 8.55% NFound: 69.93% C 9.37% H 8.46% N

EXAMPLE 100erythro-N-{1,3-Diacetyloxy-1-[6-(1-undecynyl)-2-pyridinyl]-2-propanyl}acetamide

A diastereomeric mixture ofN-{1,3-dihydroxy-1-[6-(1-undecynyl)-2-pyridinyl]-2-propanyl}acetamide(12.0 g, 4:1 erythro:threo), acetic anhydride (20.4 g), triethylamine(30.4 g), and 4-dimethylaminopyridine (0.41 g) in tetrahydrofuran (125ml) was stirred at room temperature overnight. The reaction mixture wasevaporated, methanol was added, and the solution was warmed at 50° C.for 20 min and evaporated. A 7.5% sodium bicarbonate solution was addeduntil pH 8.5, and the mixture was extracted into chloroform. The extractwas dried over anhydrous magnesium sulfate, filtered, and the filtratewas concentrated. The residue was purified by flash chromatography,eluting with 1:1-hexane:ethyl acetate. The appropriate fractions werecombined and concentrated to yield 3.5 g (24%) of product, mp 69°-71° C.

Analysis: Calculated for C₂₅ H₃₆ N₂ O₅ : 67.54% C 8.16% H 6.30% N Found:67.65% C 8.23% H 6.18% N

EXAMPLE 101 3-(1-Undecynyl)benzaldehyde

A mixture of 3-bromobenzaldehyde (51.8 g), 1-undecyne (48.6 g),bis(triphenylphosphine)palladium(II)chloride (3.37 g), copper iodide(457 mg), and triethylamine (196 ml) in dry tetrahydrofuran (300 ml) wasstirred for 4 hrs at 55° C. The reaction mixture was filtered, thefiltrate was diluted with ethyl acetate, and the solution was washedwith water and brine. The organic phase was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was chromatographed on 300 g of silica gel (1:4-ethylacetate:hexane). The appropriate fractions were collected andevaporated. Distillation of a 40-g sample of the residue (81.3 g) gave9.5 g (13%) of the product, bp 172°-174° C. (0.5 mm mercury).

Analysis: Calculated for C₁₈ H₂₄ O: 84.32% C 9.44% H Found: 84.76% C9.57% H

EXAMPLE 102 erythro-2-Amino-1-(3-undecynylphenyl)-1,3-propanediolAcetate

A solution oferythro-N-{1,3-diacetyloxy-1-[3-(undecynylphenyl-2-propanyl}acetamide(2.76 g) and aqueous 2N sodium hydroxide solution (62 ml) in ethanol (20ml) was warmed to 60° C. for 16 hr. The reaction mixture was allowed tocool to room temperature and extracted with chloroform. The extract wasdried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was chromatographed on silica gel(eluted with 900:100:5 chloroform:methanol:ammonium hydroxide). Theresidue was rechromatographed (eluted with 9:1-chloroform:methanol) toafford 1.35 g (71%) of the free base.

To a solution of free base (1.05 g) in dichloromethane (10 ml) was addedglacial acetic acid (2 ml) followed by hexane (50 ml). The mixture wasconcentrated in vacuo and the solid was recrystallized from ethylacetate to afford 860 mg (69%) of product, mp 110°-112° C.

Analysis: Calculated for C₂₂ H₃₅ NO₄ : 69.99% C 9.34% H 3.71% N Found:70.36% C 9.32% H 3.69% N

EXAMPLE 103 erythro-2-Amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediolAcetate

erythro-N-{1,3-Dihydroxy-1-[3-(1-dodecynyl)-phenyl]-2-propanyl}acetamide(2.7 g), 2N sodium hydroxide solution (36 ml) and ethanol (20 ml) wereheated at 60° C. for 19 hrs, under nitrogen. The reaction mixture wascooled, and extracted with chloroform. The extract was washed withhalf-saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. The residue waschromatographed on silica gel, eluting with 950:50:3chloroform:methanol:2N ammonium hydroxide. The appropriate fractionswere collected and evaporated. The residue was dissolved indichloromethane and treated with glacial acetic (0.27 ml). The mixturewas concentrated in vacuo and the solid was recrystallized from ethylacetate to give 1.72 g (61%) of product, mp 104°-105.5° C.

Analysis: Calculated for C₂₃ H₃₇ NO₄ : 70.55% C 9.52% H 3.58% N Found:70.62% C 9.46% H 3.54% N

EXAMPLE 104erythro-N-{1,3-Diacetyloxy-1-[3-(1-undecynyl)-1-phenyl]-2-propanyl}acetamide

To a solution oferythro-N-{1-[3-(1-undecynyl)phenyl]-1,3-dihyroxy-2-propanyl}acetamide(10:1/erythro:threo) in tetrahydrofuran (80 ml) was added aceticanhydride (9.6 ml), triethylamine (21.3 ml), and 4-dimethylaminopyridine(0.21 g). The mixture was stirred for three days at room temperature,then methanol (100 ml) was added, and the solution was warmed to 50° C.for 20 mins. The mixture was concentrated in vacuo and partitionedbetween dichloromethane and sodium bicarbonate solution. The organicphase was separated, dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was flash chromatographed over silicagel (eluted with chloroform:methanol/12:1). The appropriate fractionswere collected and concentrated. The reside was flash chromatographed asecond time over silica gel (eluted with ethyl acetate:hexane/1:2) Theappropriate fractions were collected and concentrated to afford 4.9 g(64%) of product.

ANALYSIS: Calculated for C₂₆ H₃₇ NO₅ : 70.40% C 8.41% H 3.16% N Found:70.60% C 8.52% H 3.15% N

EXAMPLE 105erythro-N-{4-[3-(1-undecynyl)phenyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide

To a solution oferythro-N-{1,3-dihydroxy-1-[3-(1-undecynyl)phenyl]-2-propanyl}acetamide(10:1,erythro/threo) (5.6 g) in dichloromethane (100 ml) was addedp-toluenesulfonic acid (3.3 g). The reaction mixture was stirred at roomtemperature overnight, diluted with dichloromethane and washed withsaturated sodium bicarbonate solution. The organic phase was dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waschromatographed over silica gel (eluted withdichloromethane/methanol/14:1). The appropriate fractions were collectedand evaporated. The residue was crystallized from ethanol/water/1:1 toafford 2.13 g (34%) of product, mp 90°-92° C.

ANALYSIS: Calculated for C₂₅ H₃₇ NO₃ : 75.15% C 9.33% H 3.51% N Found:74.59% C 9.43% H 3.51% N

EXAMPLE 106 Ethylerythro-2-acetamido-3-hydroxy-3-[2-fluoro-3-(1-undecynyl)phenyl]propionate

To a solution of 2-fluoro-3-(1-undecynyl)benzaldehyde (4.0 g) intetrahydrofuran (20 ml) was added acetamidomalonate monoethyl ester(2.84 g) and triethylamine (2.1 ml). The reaction mixture was stirredfor 3 days at room temperature. Additional acetamidomalonate monoethylester (1.4 g) and triethylamine (1.0 ml) were added, with stirring. Themixture was stirred for 3 additional days and concentrated in vacuo. Theresidue was flash chromatographed over silica gel (eluted with ethylacetate/hexane/1:1). The appropriate fractions were collected andevaporated. The residue was crystallized fromdichloromethane/hexane/1:10 to afford 3.30 g (54%) of product, mp81°-82° C.

ANALYSIS: Calculated for C₂₄ H₃₄ FNO₄ : 68.71% C 8.17% H 3.34% N Found:68.90% C 8.37% H 3.38% N

EXAMPLE 107erythro-N-{1,3-Diacetyloxy-1-[3-(1-dodecynyl)-2-fluorophenyl]-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-3-[2-fluoro-3-(1-dodecynyl)phenyl]propionate(18:1/erythro:threo) (25.7 g) in tetrahydrofuran (250 ml) at 0° C. wasadded dropwise 2M lithium borohydride in tetrahydrofuran (37 ml). Thereaction mixture was stirred at room temperature overnight, quenchedwith a solution water (50 ml), methanol (50 ml) and glacial acetic acid(2 ml), and concentrated in vacuo. The residue was extracted with ethylacetate. The organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuoto afford 22.9 g oferythro-N-{1-[3-(1-dodecynyl)-2-fluorophenyl-1,3-dihydroxy]-2-propanyl}acetamide.

To a solution of the acetamidodiol (22.1 g) in tetrahydrofuran (150 ml)was added acetic anhydride (32.8 ml) followed by triethylamine (73 ml)and 4-dimethylaminopyridine (730 mg). The reaction mixture was stirredat room temperature for 24 hrs, and methanol (50 ml) was added. Themixture was concentrated, diluted with ethyl acetate, and the solutionwas washed with saturated sodium bicarbonate solution. The aqueous phasewas separated and extracted with ethyl acetate. The organic phases werecombined, dried over anhydrous magnesium sulfate, filtered, and thefiltration was concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with 2:1/heptane:ethyl acetatefollowed by 1:1/heptane:ethyl acetate) to afford 19.9 g (71%) ofproduct.

ANALYSIS: Calculated for C₂₇ H₃₈ FNO₅ : 68.19% C 8.05% H 2.95% N Found:67.66% C 7.87% H 3.35% N

EXAMPLE 108erythro-2-Amino-1-[2-fluoro-3-(1-dodecynyl)phenyl]-1,3-propanediolAcetate

To a solution oferythro-N-{1,3-diacetyloxy-1-[3-(1-dodecynyl)-2-fluorophenyl]-2-propanyl}acetamide(6.0 g) in ethanol (50 ml) was added 25% aqueous sodium hydroxidesolution (20 ml). The mixture was heated under reflux for 3 hrs, allowedto cool to room temperature, and stirred overnight. The mixture wasdiluted with ethyl acetate and washed with water. The aqueous phase wasextracted with ethyl acetate, and the organic phases were combined,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. To a solution of the residue in ethylacetate:heptane/2:5 was added glacial acetic acid (1 ml). The solutionwas cooled to 0° C. The precipitate was recrystallized from ethylacetate to afford 3.23 g (62%) of product, mp 115°-116° C.

ANALYSIS: Calculated for C₂₃ H₃₆ FNO₄ : 67.45% C 8.86% H 3.42% N Found:67.47% C 8.58% H 3.43% N

EXAMPLE 109 Ethylerythro-2-acetamido-3-hydroxy-3-[2-fluoro-3-(1-dodecynyl)phenyl]propionate

To a solution of 2-fluoro-3-(1-dodecynyl)benzaldehyde (30.7 g) intetrahydrofuran (150 ml) was added acetamidomalonic acid monoethyl ester(20.1 g) followed by triethylamine (14.8 ml). The mixture was stirredfor 48 hrs at room temperature, and additional acetamidomalonic acidmonoethyl ester (10 g) and triethylamine (7.4 ml) were added. Thereaction mixture was stirred for 24 hr, concentrated in vacuo, and theresidue was flash chromatographed over silica gel (eluted with ethylacetate:heptane/1:1). The appropriate fractions were collected andevaporated. The residue was crystallized from ethyl acetate/heptane/1:5to give 31.1 g (68%) of product, mp 84°-86° C.

ANALYSIS: Calculated for C₂₅ H₃₆ FNO₄ : 69.26% C 8.37% H 3.23% N Found:69.54% C 8.40% H 3.26% N

EXAMPLE 110erythro-2-Amino-1-[5-(1-undecynyl)-2-thienyl]-1,3-propanediol Acetate

A solution oferythro-N-[1-[5-(1-undecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(15.0 g), 2N sodium hydroxide solution (150 ml) and 95% ethanol (100 ml)was stirred at 65° C. overnight. The reaction mixture was evaporated,and the aqueous residue was neutralized with glacial acetic acid. Thesolution was diluted with water (200 ml) and extracted with 4:1chloroform-isopropanol. The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed (silica; 90:9:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and evaporated. The residue was dissolved in ethanol andtreated with an excess of glacial acetic acid. The solvent wasevaporated, and the salt was crystallized from ethyl acetate to give11.4 g (72%) of product, mp 109°-111° C.

ANALYSIS: Calculated for C₂₀ H₃₃ NO₄ S: 62.63% C 8.67% H 3.65% N Found:62.46% C 8.41% H 3.63% N

EXAMPLE 111erythro-1-[5-(1-Undecynyl)-2-thienyl]-1-(2-phenyl-4-oxazolinyl)methanol

A solution oferythro-2-amino-1-[5-(1-undecynyl)-2-thienyl]-1,3-propanediol (5.00 g),milled potassium carbonate (0.33 g), glycerol (5 ml), and ethyleneglycol (10 ml) was heated to 110° C., with stirring. Benzonitrile (2.66g) was added, and the solution stirred at 110° C., under nitrogen,overnight. The reaction mixture was poured into water (300 ml) andextracted with ethyl acetate. The combined organic extracts were driedore anhydrous sodium sulfate, filtered, and the filtrate was evaporated.The residue was flash chromatographed (silica; 3:1 hexane/ethylacetate). The appropriate fractions were collected and evaporated. Theresidue was recrystallized from ether-hexane to give 4.6 g (73%) ofproduct, mp 99°-100° C.

ANALYSIS: Calculated for C₂₅ H₃₁ NO₂ S: 73.31% C 7.63% H 3.42% N Found:73.17% C 7.60% H 3.37% N

EXAMPLE 112erythro-N-[1-[4-(1-Dodecenyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[4-(1-dodecenyl)-2-thienyl]-3-hydroxypropionate(10.0 g) in dry tetrahydrofuran (50 ml) was stirred at 0° C. undernitrogen as 2.0M lithium borohydride (18 ml) in tetrahydrofuran wasadded dropwise. The reaction mixture was stirred under a nitrogenatmosphere for three hrs, warming to 15° C. A solution of methanol (24ml), water (20 ml), and acetic acid (3 ml) was added, with cooling in anice bath. The solution was neutralized with glacial acetic acid andevaporated. The residue was diluted with water (200 ml) and extractedwith ethyl acetate. The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed (silica: 5% methanol/dichloromethane).The appropriate fractions were collected and evaporated. The residue wascrystallized from ether-hexane and then triturated with hexane to give6.9 g (77%) of product, mp 87°-90° C.

ANALYSIS: Calculated for C₂₁ H₃₅ NO₃ S: 66.10% C 9.25% H 3.67% N Found:66.25% C 9.24% H 3.68% N

EXAMPLE 113 Ethylerythro-2-acetamido-3-hydroxy-3-[5-(1-tridecynyl)-2-thienyl]-propionate

A solution of 5-(1-tridecynyl)-2-thiophenecarboxaldehyde (49.6 g),acetamidomalonic acid monoethyl ester (35.5 g) and triethylamine (26 ml)in dry tetrahydrofuran (175 ml) was stirred, under nitrogen, at ambienttemperature for 3.5 days. Additional amounts of acetamidomalonatemonoethyl ester (32.3 g) and triethylamine (24 ml) were added, and themixture was stirred for 6 days. The reaction mixture was evaporated, andthe residue was dissolved in ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was recrystallized twice from hexane:ethylacetate/1:1, then from ethyl acetate to give 25.7 g (34.5%) of product,mp 83°-84.5° C.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₄ S: 66.17% C 8.56% H 3.22% N Found:66.06% C 8.98% H 3.12% N

EXAMPLE 114erythro-N-{1,3-Dihydroxy-1-[5-(1-tridecynyl)-2-thienyl]-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-3-[5-(1-tridecynyl)-2-thienyl]propionate(34.8 g) in dry tetrahydrofuran (250 ml) was added slowly 2.0M lithiumborohydride/tetrahydrofuran (40 ml) at 0° C., under nitrogen, withstirring at ambient temperature overnight. The reaction mixture waschilled, and methanol/water/1:1 (50 ml) was added slowly followed byglacial acetic acid (5.1 ml) in methanol/water/1:1 (50 ml). The solutionwas stirred at ambient temperature for 1 hr, evaporated, and the residuewas azeotroped with methanol. Saturated sodium bicarbonate solution wasadded until pH 8 was obtained, and the mixture was extracted with ethylacetate. The extracts were dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was flashchromatographed on silica gel eluting with ethyl acetate/methanol (0.5%to 2%). The appropriate fractions were collected and evaporated. Theresidue was recrystallized from ethyl acetate to give 23.4 g (74.4%) ofproduct, mp 94°-95° C.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₃ S: 67.14% C 8.96% H 3.56% N Found:67.37% C 9.49% H 3.57% N

EXAMPLE 115erythro-2-Amino-1-[5-(1-tridecynyl)-2-thienyl]-1,3-propanediol Acetate

A mixture oferythro-N-{1,3-dihydroxy-1-[5-(1-tridecynyl)-2-thienyl]-2-propanyl}acetamide(11.8 g), 2N sodium hydroxide solution (105 ml), and ethanol (70 ml) washeated at 60° C., under nitrogen, for 22 hrs. The reaction mixture wascooled and extracted with chloroform. The extracts were washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel eluting with chloroform/methanol/2Nammonium hydroxide/950:50:3 to 925:75:4. The appropriate fractions werecollected and evaporated. The residue was dissolved in ethyl acetate(100 ml), acetic acid (1.5 ml) was added, and the mixture was chilled toyield 10.0 g (81.1%) of product, mp 106°-108° C.

ANALYSIS: Calculated for C₂₀ H₃₃ NO₂ S.C₂ H₄ O₂ : 64.20% C 9.06% H 3.40%N Found: 63.87% C 8.96% H 3.35% N

EXAMPLE 116 Ethylerythro-2-acetamido-3-[2-(1-dodecynyl)-4-thienyl]-3-hydroxypropionate

A solution of 2-(1-dodecynyl)-4-thiophenecarboxaldehyde (27.6 g),acetamidomalonic acid monoethyl ester (18.9 g), and triethylamine (11.1g) in dry tetrahydrofuran (100 ml) was stirred, under nitrogen, for 1week. Acetamidomalonic acid monoethyl ester (18.9 g) and triethylamine(11.1 g) were added in two portions over the next three days, and thereaction mixture was stirred an additional week. The reaction mixturewas evaporated, ethyl acetate was added, and the mixture was washed withsaturated sodium bicarbonate solution and sodium chloride solution,dried over magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was recrystallized from heptane/ethylacetate/2:1 to give 15.3 g (36.3%) of the product, mp 71°-72.5° C.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₄ S: 65.53% C 8.37% H 3.32% N Found:65.75% C 8.38% H 3.28% N

EXAMPLE 117erythro-N-{1-[2-(1-Dodecynyl)-4-thienyl]-1,3-dihydroxy-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-[2-(1-dodecynyl)-4-thienyl]-3-hydroxypropionate(17.7 g) in dry tetrahydrofuran (125 ml) was added slowly 2M lithiumborohydride/tetrahydrofuran (18 ml) at 4° C., under nitrogen, withstirring. The reaction mixture was stirred at room temperature over theweekend, chilled, and methanol/water/1:1 (30 ml) was added slowly,followed by glacial acetic acid (2.3 ml) in methanol/water/1:1 (30 ml).The solution was stirred at ambient temperature for 1 hr, evaporated,and azeotroped with methanol. Ethyl acetate was added, then saturatedsodium bicarbonate solution until a pH 8 was obtained, and the mixturewas extracted with ethyl acetate. The organic extracts were dried,filtered, and the filtrate was concentrated. The residue wasrecrystallized from ethyl acetate to give 9.80 g (61.5%) of product, mp97.5°-98.5° C.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₃ S: 66.45% C 8.76% H 3.69% N Found:66.56% C 8.86% H 3.64% N

EXAMPLE 118erythro-2-Amino-1-[2-(1-dodecynyl)-4-thienyl]-1,3-propanediol

A mixture oferythro-N-{1-[2-(1-dodecynyl)-4-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(10.4 g), 2N sodium hydroxide solution (69 ml) and ethanol solution (35ml) was heated at 60° C., under nitrogen, for 22 hrs. The reactionmixture was cooled, water was added, and the mixture was extracted withchloroform. The extracts were washed with brine, dried over magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide/950:50:3 to 925:75:4. The appropriate fractions werecollected and evaporated to give 7.47 g (81%) of product. A 1.8g-portion of the product was recrystallized from ethyl acetate to yieldthe analytical sample, mp 69°-70° C.

ANALYSIS: Calculated for C₁₉ H₃₁ NO₂ S: 67.61% C 9.26% H 4.15% N Found:67.94% C 9.42% H 4.11% N

EXAMPLE 119erythro-2-Amino-1-[2-(1-dodecynyl)-4-thienyl]-1,3-propanediol Acetate

A mixture oferythro-N-{1-[2-(1-dodecynyl)-4-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(10.4 g), 2N sodium hydroxide solution (69 ml), and ethanol (35 ml) washeated at 60° C., under nitrogen, for 22 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide solution/950:50:3 to 925:75:4. The appropriatefractions were collected and evaporated to give 7.47 g (81%) of productas the free base. A 1.9 g-portion was dissolved in ethyl acetate, aceticacid (0.32 ml) was added, and the solution was chilled to yield 1.9 g(69.2%) of product, mp 124°-125° C.

ANALYSIS: Calculated for C₂₁ H₃₅ NO₄ S: 63.44% C 8.87% H 3.52% N Found:63.35% C 8.81% H 3.35% N

EXAMPLE 120erythro-2-Amino-1-[2-(1-dodecynyl)-4-thienyl]-1,3-propanediol Maleate

A solution oferythro-N-{1-[2-(1-dodecynyl)-4-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(10.4 g), 2N sodium hydroxide solution (69 ml), and ethanol (35 ml) wereheated at 60° C., under nitrogen, for 22 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide solution/950:50:3 to 925:75:4. The appropriatefractions were collected and evaporated to give 7.47 g (81%) of productas the free base. A 1.7 g-portion was dissolved in ethyl acetate andmaleic acid (0.58 g) was added. The solution was chilled, and theprecipitate was collected to yield 1.9 g (68%) of product, mp 101°-103°C.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₆ S: 60.90% C 7.78% H 3.09% MN Found:60.98% C 7.78% H 3.11% N

EXAMPLE 121erythro-N-{1-[5-(1-Dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl}-N-ethylacetamide

Toerythro-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(2.1 g) in ether/tetrahydrofuran/4:1 (100 ml) was added lithium aluminumhydride (0.21 g) at 5° C., under nitrogen, and the mixture was stirredat ambient temperature overnight. Additional amounts of lithium aluminumhydride (0.21, 0.33, and 0.21 g) were added. The mixture was chilled,and saturated ammonium chloride solution was added. The pH was adjustedto 8.5 with 7.5% sodium bicarbonate solution, and the solution wasextracted with ethyl acetate. The extracts were washed with brine, driedover magnesium sulfate, filtered, and the filtrate was concentrated. Thereside was flash chromatographed on silica gel, eluting withchloroform/methanol/2N ammonium hydroxide solution/960:40:2.5. Theappropriate fractions were evaporated to give 1.3 g of a mixture oferythro-1-[5-(1-dodecynyl)-2-thienyl]-2-N-ethylamino-1,3-propanediol andstarting material (about 6:1).

To the mixture (1.3 g) was added acetic anhydride (2.3 g), triethylamine(3.4 g), and 4-dimethylaminopyridine (0.05 g) in tetrahydrofuran (30ml), and the mixture was stirred overnight. The mixture was evaporated,azeotroped with toluene, warmed with methanol for 20 mins, andreevaporated. Water and 7.5% sodium bicarbonate solution were added topH 8.5, and the mixture was extracted with chloroform. The extracts werewashed with brine, dried over magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was flash chromatographed onsilica gel, eluting with heptane/ethyl acetate/4:1 to 2:1. Theappropriate fractions were collected and evaporated to give 1.5 g (73%yield, 44.4% for 2 steps) oferythro-N-{1,3-diacetyloxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}-N-ethylacetamide.

A mixture oferythro-N-{1,3-diacetyloxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}-N-ethylacetamide(1.4 g), anhydrous potassium carbonate (0.04 g) in methanol (25 ml) wasallowed to stand for 3 hrs. Water was added and the mixture wasextracted with dichloromethane. The extracts were washed with brine,dried over magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was chromatographed on a silica gel columneluting with ethyl acetate to give 0.93 g (81.6% yield, 36.6% overallfor 3 steps) of product.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₃ S: 67.77% C 9.15% H 3.44% N Found:67.24% C 9.45% H 3.31% N

EXAMPLE 122 erythro-2-Amino-1-[5-(dodecynyl)-2-thienyl]1,3-propanediolAcetate

A solution oferythro-N-{1,3-dihydroxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}acetamide(45.6 g), 2N sodium hydroxide solution (300 ml), and ethanol (150 ml)was heated at 60° C., under nitrogen, for 20 hrs. The reaction mixturewas cooled, extracted with chloroform, and the extract was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide/900:100:5. The appropriate fractions were collectedand evaporated to give 38.3 g (94.5%) of product as the free base. A 3.3g-portion of product free base was dissolved in ethyl acetate, aceticacid (0.6 ml) was added, and the solution was chilled to yield 3.3 g(80.2% yield) of product, mp 113°-116°.

ANALYSIS: Calculated for C₁₉ H₃₁ NO₂ S.C₂ H₄ O₂ : 63.44% C 8.87% H 3.52%N Found: 63.37% C 8.95% H 3.51% N

EXAMPLE 123erythro-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(22.8 g), 2N sodium hydroxide solution (150 ml), and ethanol (75 ml) washeated at 60° C., under nitrogen, for 19 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide/925:75:4 to 900:100:5. The appropriate fractions werecollected and evaporated to give 18.6 g (92%) of product free base. A 5g-portion of product free base was dissolved in ethyl acetate,hydrochloric acid (1.4 ml) in ethanol was added, and the solution wasevaporated. The residue was recrystallized from ethyl acetate to yield4.4 g (73.4%) of product, mp 163°-167° C.

ANALYSIS: Calculated for C₁₉ H₃₁ NO₂ S.HCl: 61.02% C 8.62% H 3.75% NFound: 60.74% C 8.89% H 3.73% N

EXAMPLE 124erythro-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol Maleate

A solution oferythro-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(22.8 g), 2N sodium hydroxide solution (150 ml), and ethanol (75 ml) washeated at 60° C., under nitrogen, for 19 hrs. The reaction mixture wascooled, water was added, and the solution was extracted with chloroform.The extracts were washed with brine, dried over magnesium sulfate,filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform/methanol/2Nammonium hydroxide/925:75:4 to 900:100:5. The appropriate fractions werecollected and evaporated to give 18.6 g (92%) of product free base. A 9g-portion of product free base was dissolved in ethyl acetate, maleicacid (3.1 g) was added, and the solution was chilled to yield 10.9 g(83.2% yield) of product, mp 120°-121° C.

ANALYSIS: Calculated for C₁₉ H₃₁ NO₂ S.C₄ H₄ O₄ : 60.90% C 7.78% H 3.09%N Found: 60.89% C 7.94% H 2.97% N

EXAMPLE 125erythro-1-[5-(1-Dodecynyl)-2-thienyl]-2-ethylamino-1,3-propanediol

To a solution oferythro-N-{1,3-dihydroxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}acetamide(11.9 g) in dry tetrahydrofuran (240 ml) chilled to 5° C., lithiumaluminum hydride (1.2 g) was added slowly over 2 hrs, under nitrogen.The mixture was allowed to warm to room temperature and was stirredovernight. Lithium aluminum hydride (2.4 g) was added at roomtemperature during the next day, and the mixture was stirred for threedays. The reaction mixture was chilled, quenched with saturated ammoniumchloride solution to pH 8, and the mixture was extracted with ethylacetate. The organic extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue product was chromatographed twice on silicagel eluting with chloroform/methanol/2N ammonium hydroxide/970:30:2. Theappropriate fractions were collected and concentrated to give 1.5 g(13.2%) of product, mp 48°-50° C.

ANALYSIS: Calculated for C₂₁ H₃₅ NO₂ S: 69.00% C 9.65% H 3.83% N Found:69.00% C 9.61% H 3.82% N

EXAMPLE 126erythro-1,1-Dimethylethyl-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxyl-2-propanyl}-N-methylcarbamate

To a solution oferythro-1,1-dimethylethyl-N-{1,3-diacetyloxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}carbamate(8.24 g) in dry dimethylformamide (90 ml) sodium hydride (0.52 g, 80%immersion in oil) was added with stirring, under nitrogen. The mixturewas stirred for 30 mins. Methyl iodide (2.47 g) was added, and themixture was stirred at ambient temperature overnight. The reactionmixture was concentrated, water and 7.5% sodium bicarbonate were addedto pH 8.5, and the mixture was extracted with chloroform. The extractswere filtered, washed with brine, dried over magnesium sulfate,filtered, and the filtrate was concentrated to provideerythro-1,1-dimethylethyl-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-diacetyloxy-2-propanyl}-N-methylcarbamate.

A mixture of theerythro-1,1-dimethylethyl-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-diacetyloxy-2-propanyl}-N-methylcarbamate in methanol (150 ml) and potassium carbonate (0.44 g) wasstirred for 3 hrs. The mixture was washed with brine, dried overmagnesium sulfate, filtered, and the filtrate was evaporated. Theresidue was combined with the residue from similar reactions carried outon 18.6 mmol scales and flash chromatographed twice on silica geleluting with heptane/ethyl acetate/2:1. The appropriate fractions werecollected and evaporated to give 2.0 g (13.0%) of product.

ANALYSIS: Calculated for C₂₅ H₄₁ NO₄ S: 66.48% C 9.15% H 3.10% N Found:66.26% C 9.29% H 2.98% N

EXAMPLE 127erythro-1,1-Dimethylethyl-N-{1,3-diacetyloxy-1-[5-(1-dodecynyl)-2-thienyl]-2-propanyl}carbamate

A solution oferythro-1,1-dimethylethyl-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanyl}carbamate(7.7 g), acetic anhydride (7.2 g), triethylamine (10.7 g), and4-dimethylaminopyridine (0.22 g) in tetrahydrofuran (100 ml) was allowedto stand at room temperature for 1 hr. The reaction mixture wasevaporated. The residue was warmed with methanol for 20 min, and thesolution was evaporated. Water was added to the residue, the pH adjustedwith saturated sodium bicarbonate solution and ammonium hydroxide to pH8.5, and the solution was extracted with chloroform. The extracts werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was flash chromatographed onsilica gel eluting with heptane/ethyl acetate/9:1. The appropriatefractions were collected and evaporated to give 5.2 g (55.9%) ofproduct, mp 85°-86.5° C.

ANALYSIS: Calculated for C₂₈ H₄₃ NO₆ S: 64.46% C 8.31% H 2.68% N Found:64.69% C 8.48% H 2.68% N

EXAMPLE 128erythro-4-{[5-(1-Dodecynyl)-2-thienyl]hydroxymethyl}-2-oxazolidinone

Toerythro-1,1-dimethylethyl-N-{1,3-diacetyloxy-1-[5-(1-dodecynyl)-2-thienyl]-1-propanyl}carbamate(8.24 g) dissolved in dimethylformamide (90 ml), under nitrogen, wasadded sodium hydride (0.52 g, 80% immersion in oil), with stirring, over30 mins, followed by methyl iodide (2.47 g). The reaction mixture wasstirred at room temperature overnight and evaporated. Water and 7.5%sodium bicarbonate solution were added to pH 8.5, and the mixture wasextracted with chloroform. The extracts were washed with brine, driedover magnesium sulfate, filtered, and the filtrate was concentrated. Tothe residue in methanol (150 ml) was added and potassium carbonate (0.44g), with stirring over 3 hrs. The mixture was extracted with chloroform.The extracts were washed with brine, dried over magnesium sulfate,filtered, and the filtrate was evaporated. The residue was flashchromatographed twice on silica gel, eluting with heptane/ethylacetate/2:1. The appropriate fractions were collected and evaporated.The residue was recrystallized from heptane/ethyl acetate/6:1 to give0.37 g (4.0%) of product, mp 101°-103° C.

ANALYSIS: Calculated for C₂₁ H₃₁ NO₃ S: 66.81% C 8.28% H 3.71% N Found:67.10% C 8.21% H 3.64% N

EXAMPLE 129 Ethylthreo-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate

A mixture of ethylthreo-5-[4-(1-dodecynyl)-2-thienyl]-2-methyl-4,5-dihydro-4-oxazolecarboxylate(3.90 g) and 50% of aqueous acetic acid (100 ml) was stirred at 50° C.overnight. The reaction mixture was cooled to room temperature, and thepH was adjusted to 6 with sodium bicarbonate solution. The suspensionwas extracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue wasrecrystallized from ether and from ethyl acetate/heptane to give 3.7 g(91%) of product, mp 102°-103° C.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₄ S: 65.53% C 8.37% H 3.32% N Found:65.05% C 8.44% H 3.29% N

EXAMPLE 130erythro-N-[1-[4-(1-Dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate(3.70 g) in dry tetrahydrofuran (100 ml) was stirred at 0° C., undernitrogen, as lithium borohydride (2.0M, tetrahydrofuran) (5.7 ml) wasadded dropwise. The reaction mixture was stirred under a nitrogenatmosphere for three hrs, cooled to 0° C., and methanol (20 ml), water(20 ml), acetic acid (3 ml) solution was added dropwise. The solutionwas neutralized with glacial acetic acid and evaporated. The residue wasdiluted with water (200 ml) and extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was flashchromatographed (silica; 4% methanol/dichloromethane). The appropriatefractions were collected and evaporated. The residue was crystallizedfrom ether to give 2.4 g (72%) of product, mp 69°-72° C.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₃ S: 66.45% C 8.76% H 3.69% N Found:66.43% C 8.81% H 3.69% N

EXAMPLE 131 threo-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolMaleate

A solution ofthreo-N-[1-[4-(dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(1.53 g), 2N sodium hydroxide solution (100 ml), and 95% ethanol (75 ml)was stirred at 50° C. over the weekend. The reaction mixture wasevaporated and the residue diluted with ammonium chloride solution (300ml). The mixture was extracted with ethyl acetate, and the combinedorganic extracts were dried over anhydrous sodium sulfate, filtered, andthe filtrate was evaporated. The residue was flash chromatographed(silica; 90:9:1 dichloromethane/methanol/ammonium hydroxide solution).The appropriate fractions were collected and evaporated. The residue wasdissolved in ethyl acetate, and maleic acid was added. Heptane wasadded, and the precipitate was collected and recrystallized from ethylacetate/heptane to give 1.1 g (60%) of product, mp 133°-136° C.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₆ S: 60.90% C 7.78% H 3.09% N Found:60.77% C 7.63% H 3.12% N

EXAMPLE 132erythro-2-Dimethylamino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolMaleate

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (4.00 g),37% aqueous formaldehyde (9 ml), and acetonitrile (100 ml) was stirredat room temperature for one hr, then sodium cyanoborohydride (2.23 g)and tetrahydrofuran (40 ml) were added, and the reaction mixture wasstirred at room temperature for 2.5 hrs. 50% Aqueous acetic acid wasadded until the mixture was slightly acidic, and the mixture was stirred30 mins. The mixture was evaporated, the residue diluted to 400 ml withwater, basified with ammonium hydroxide, and the mixture was extractedwith chloroform. The extracts were washed with brine, the layers wereseparated, and the organic phase was dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed (silica; 8% methanol/dichloromethane). Theappropriate fractions were combined and evaporated to give 3.0 g (69%)of product free base. A 1.25 g-sample of product free base was dissolvedin ether and treated with maleic acid (1.05 equiv). Ethyl acetate (about2 ml) was added, then heptane was added to the cloud point, and thesuspension was cooled to give 1.2 g of product, mp 59°-61° C.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₆ S: 62.34% C 8.16% H 2.91% N Found:61.95% C 8.12% H 2.90% N

EXAMPLE 133erythro-N-[1-[4-(1-Dodecynyl)-2-thienyl]-3-hydroxy-1-methoxy-2-propyl]benzamide

A mixture oferythro-4-[[4-(1-dodecynyl)-2-thienyl]-2-methoxymethyl]-2-phenyloxazoline(4.20 g) and 50% aqueous acetic acid (60 ml) was stirred at 50° C.overnight. The reaction mixture was cooled to room temperature, dilutedwith water (300 ml), and the pH was adjusted to 6 with sodiumbicarbonate solution. The suspension was extracted with ethyl acetate.The extracts were dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated. The residue was flash chromatographed (silica;2:1 heptane/ethyl acetate). The appropriate fractions were collected andevaporated. The residue was crystallized from ethyl acetate/heptane togive 3.2 g (73%) of product, mp 62°-64° C.

ANALYSIS: Calculated for C₂₇ H₃₇ NO₃ S: 71.17% C 8.18% H 3.07% N Found:71.11% C 8.18% H 2.89% N

EXAMPLE 134erythro-2-Amino-3-[4-(1-dodecynyl)-2-thienyl]-3-methoxypropanol Maleate

A solution oferythro-N-[1-[4-(dodecynyl)-2-thienyl]-3-hydroxy-1-methoxy-2-propyl]benzamide(2.10 g), 2N sodium hydroxide solution (100 ml), and 95% ethanol (75 ml)was stirred at 70° C. for two days. The reaction mixture was evaporated,the residue diluted with ammonium chloride solution (300 ml), andextracted repeatedly with ethyl acetate. The combined organic extractswere dried over anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed (silica, 8%methanol/dichloromethane). The appropriate fractions were collected andevaporated. Maleic acid was added to the residue dissolved in ethylacetate. Heptane was added. The precipitate was collected andrecrystallized from ethyl acetate to give 1.4 g (65%) of product, mp108°-109° C.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₆ S: 61.64% C 7.89% H 3.00% N Found:61.61% C 7.67% H 2.67% N

EXAMPLE 135erythro-1-[4-(1-Dodecynyl)-2-thienyl]-1-(2-phenyl-4-oxazolinyl)methanol

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (10.0 g),milled potassium carbonate (0.63 g), glycerol (15 ml) and ethyleneglycol (15 ml) was heated to 100° C., with stirring. Benzonitrile (5.09)was added, and the solution was stirred at 110° C., under nitrogen,overnight. The reaction mixture was poured into water (500 ml) andextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was purified by flash chromatography (silica;5:2 heptane/ethyl acetate). The appropriate fractions were collected andevaporated. The residue was recrystallized from ether to give 8.0 g(64%) of product, mp 105°-107° C.

ANALYSIS: Calculated for C₂₆ H₃₃ NO₂ S: 73.72% C 7.85% H 3.31% N Found:73.74% C 7.94% H 3.28% N

EXAMPLE 136erythro-4-[[4-(1-Dodecynyl)-2-thienyl]methoxymethyl]-2-phenyloxazoline

A solution oferythro-1-(1-dodecynyl)-2-thienyl]-1-(2-phenyl-4-oxazolinyl)methanol(4.30 g) in dry dimethylformamide (75 ml) was stirred at roomtemperature, under nitrogen, as sodium hydride (256 mg) was added. Thereaction mixture was stirred, under nitrogen, at room temperature forone hr, and dimethylsulfate (1.34 g) was added dropwise. The mixture wasstirred at room temperature, under nitrogen, for one hr, poured intoammonium chloride solution (400 ml), and extracted with ethyl acetate.The extracts were dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated. The residue was flash chromatographed (silica;dichloromethane). The appropriate fractions were collected andevaporated. The residue was distilled in a kugelrohr (oventemperature=100° C./0.05 mm Hg) to give 2.7 g (61%) of product.

ANALYSIS: Calculated for C₂₇ H₃₅ NO₂ S: 74.10% C 8.06% H 3.20% N Found:73.92% C 8.05% H 3.26% N

EXAMPLE 137erythro-2-Methylamino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolMaleate

A mixture oferythro-1-[4-(1-dodecynyl)-2-thienyl]-1-(2-phenyl-4-oxazolinyl)methanol(3.00 g), iodomethane (3.02 g), and dimethylsulfoxide (35 ml) wasstirred at 30° C., under nitrogen, for seven days. The reaction mixturewas evaporated, 2N sodium hydroxide solution (45 ml) was added, andreaction mixture was stirred at 60° C. overnight. The mixture was pouredinto ammonium chloride solution (400 ml) and extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed (silica; 90:9:1 dichloromethane/methanol/ammoniumhydroxide solution). The appropriate fractions were collected andevaporated. Maleic acid in ethyl acetate was added to the residue.Heptane was added, and the salt was collected and recrystallized fromethyl acetate/heptane to give 1.9 g (57%) of product, mp 59°-61° C.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₆ S: 61.64% C 7.98% H 3.00% N Found:61.08% C 7.98% H 2.83% N

EXAMPLE 138erythro-2-Dimethylamino-3-[4-(1-dodecynyl)-2-thienyl]-3-methoxy-1-propanolMaleate

A solution oferythro-2-dimethylamino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol(3.40 g) in dry dimethylformamide (75 ml) was stirred at roomtemperature, under nitrogen, as sodium hydride (234 mg) was added. Thereaction mixture was stirred under nitrogen at room temperature for twohrs, and dimethylsulfate (1.23 g) was added dropwise. The mixture wasstirred at room temperature, under nitrogen, for two hrs, poured intoammonium chloride solution (400 ml), and extracted with ethyl acetate.The extracts were dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated. The residue was flash chromatographed (silica;4% methanol/dichloromethane). The appropriate fractions were collectedand evaporated. Maleic acid in ethyl acetate and heptane were added tothe residue. The precipitate was collected and recrystallized from ethylacetate/heptane to give 2.2 g (48%) of product, mp 69°-71° C.

ANALYSIS: Calculated for C₂₆ H₄₁ NO₆ S: 63.00% C 8.34% H 2.83% N Found:62.88% C 8.38% H 2.83% N

EXAMPLE 139erythro-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol Maleate

To a solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (1.50 g)in warm ethyl acetate (75 ml) was added a solution of maleic acid (542mg) in warm ethyl acetate. The solution was cooled and the crystalscollected. The crystals were recrystallized from ethyl acetate to give1.8 g (89%) of product, mp 120°-123° C. (softened).

ANALYSIS: Calculated for C₂₃ H₃₅ NO₆ S: 60.90% C 7.78% H 3.09% N Found:61.05% C 7.86% H 3.11% N

EXAMPLE 140erythro-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolHydrochloride

A solution oferythro-N-[1-[4-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(40.00 g), 2N sodium hydroxide solution (150 ml), and 95% ethanol (100ml) was stirred at 50° C. overnight. The reaction mixture was cooled toroom temperature and neutralized with glacial acetic acid. The mixturewas diluted with ammonium chloride solution (200 ml) and extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, and the filtrate was evaporated. The residuewas purified by flash chromatography (silica; 90:0:1dichloromethane/methanol/ammonium hydroxide solution). The appropriatefractions were collected and evaporated. Recrystallization of theresidue from ethyl acetate gave 25.2 g (71%) of product free base. Asolution of product free base (1.5 g) dissolved in ethyl acetate wasstirred at 0° C. as a slight excess of ethereal hydrogen chloride wasadded dropwise. Heptane was added and the solution was cooled. The solidwas collected and recrystallized from ethanol/ethyl acetate to give 1.2g of product, mp 115° C. (softened), 190° C. (dec).

ANALYSIS: Calculated for C₁₉ H₃₂ ClNO₂ S: 61.02% C 8.62% H 3.75% NFound: 61.35% C 8.69% H 3.66% N

EXAMPLE 141erythro-2-[1-[4-(1-Dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]-1H-isoindole-1,3(2H)-dione

A mixture oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (6.00 g)and phthalic anhydride (3.29 g) was stirred at 150° C., under nitrogen,and then placed under high vacuum for 15 mins, with stirring. Thereaction mixture was cooled, the vacuum was released, and the residuewas flash chromatographed (silica: 2% methanol/dichloromethane). Theappropriate fractions were collected, combined, and concentrated to give6.2 g (75%) of product. A sample was purified on a chromatotron (silica;5:2 heptane/ethyl acetate) to yield the analytical sample, as an oilafter drying under vacuum.

ANALYSIS: Calculated for C₂₇ H₃₃ NO₄ S: 69.35% C 7.11% H 3.00% N Found:69.07% C 7.36% H 2.83% N

EXAMPLE 142 2-(1-Dodecynyl)-4-thiophenecarboxaldehyde

A solution of 2-bromo-4-thiophenecarboxaldehyde (45.3 g), 1-dodecyne(43.4 g), and triethylamine (99 ml), in dry tetrahydrofuran (250 ml) waschilled to 5° C. and degassed under nitrogen.bis(Triphenylphosphine)palladium(II)chloride (1.66 g) andcopper(I)iodide (0.23 g) were added to the reaction mixture. The mixturewas degassed and stirred overnight, under nitrogen, as it was allowed towarm to room temperature. The precipitate was filtered off, washed withethyl acetate, and the filtrate was evaporated. Ethyl acetate was addedto the residue. The solution was washed with brine, dried over magnesiumsulfate, filtered, and the filtrate was concentrated. The residue waschromatographed through a silica gel pad eluting with heptane/1% ethylacetate. The appropriate fractions were collected and evaporated. Theresidue and that from a similar reaction on a 0.05 mole scale werecombined and distilled to give 30.7 g (79.5%), bp 181°-185° C. @0.35 mmHg.

ANALYSIS: Calculated for C₁₇ H₂₄ OS: 73.86% C 8.75% H Found: 73.55% C8.75% H

EXAMPLE 143 5-(1-Tridecynyl)-2-thiophenecarboxaldehyde

A solution of 5-bromo-2-thiophenecarboxaldehyde (34.4 g), 1-tridecyne(35.7 g), and triethylamine (75 ml) in of dry tetrahydrofuran (200 ml)was degassed under nitrogen.bis(Triphenylphosphine)palladium(II)chloride (1.3 g, 1%) andcopper(I)iodide (0.17 g, 0.5%) was added. The reaction mixture wasdegassed and stirred in a water bath at 20° C. for 1 hr, and then for 2days at ambient temperature, under nitrogen. The precipitate wascollected, washed with ethyl acetate, filtered, and the filtrate wasevaporated. The residue was taken up in ethyl acetate, washed withbrine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by flashchromatography on silica gel, eluting with hexane:1% ethyl acetate. Theappropriate fractions were collected and evaporated to yield 51.6 g ofan oil. A 2.0 g-portion was dried under high vacuum at ambienttemperature for 4 hrs to give 1.77 g (87.3% yield) of product as an oil.

ANALYSIS: Calculated for C₁₈ H₂₆ OS: 74.43% C 9.02% H Found: 74.87% C9.31% H

EXAMPLE 144 2-Fluoro-3-(1-dodecynyl)benzaldehyde

To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene intetrahydrofuran (60 ml) at -78° C. was added slowly sec-butyllithium(1.3M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30min, and dimethylformamide (2.8 ml) was added dropwise. The mixture wasstirred for 5 min at -78° C. and allowed to warm to room temperature.The mixture was diluted with ethyl acetate and washed with water. Theorganic phase was separated, dried over anhydrous magnesium sulfate,filtered, and the filtrate concentrated in vacuo. The residue was flashchromatographed on silica gel (eluted with ethyl acetate/heptane/1:10).The appropriate fractions were collected and evaporated. The residue waschromatographed a second time over silica gel (eluted withdichloromethane) to afford 7.10 g (91%) of product.

ANALYSIS: Calculated for C₁₉ H₂₅ FO: 79.13% C 8.74% H Found: 79.33% C9.05% H

EXAMPLE 145 Ethylerythro-2-acetamido-3-(5-bromo-2-thienyl)-3-hydroxypropionate

5-Bromo-2-thiophenecarboxaldehyde (3.8 g), acetamidomalonic acidmonoethyl ester (3.8 g) and triethylamine (2.9 ml) in drytetrahydrofuran (15 ml) was stirred, under nitrogen, at ambienttemperature for 3 days. Additional amounts of the malonate ester (5.7 g)and triethylamine (5.8 ml) were added over the next 2 days, withstirring. The mixture was evaporated, and the residue was dissolved inethyl acetate. The solution was washed with saturated sodium bicarbonatesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was chromatographed on silica geleluting with chloroform. The appropriate fractions were collected andconcentrated to give 3.3 g (50%) of the product, mp 118.5°-120.5° C.

ANALYSIS: Calculated for C₁₁ H₁₄ BrNO₄ S: 39.30% C 4.20% H 4.17% NFound: 39.56% C 4.06% H 3.81% N

EXAMPLE 146erythro-N-Methyl-N'-[1-[5-(1-undecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]urea

To a solution oferythro-2-amino-1-[5-(1-undecynyl)-2-thienyl]-1,3-propanediol (2.5 g)and dry dichloromethane (100 ml) was added methyl isocyanate (0.85 g),and the mixture was stirred at room temperature for 15 mins. The mixturewas evaporated. The residue was taken up in ethyl acetate, and thesolution was washed with dilute sodium bicarbonate solution and brine,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasevaporated. The residue was recrystallized from ethyl acetate/hexane togive 2.0 g (67.2%) of product, mp 97°-99° C.

ANALYSIS: Calculated for C₂₀ H₃₂ N₂ O₃ S: 63.12% C 8.48% H 7.36% NFound: 63.10% C 8.46% H 7.36% N

EXAMPLE 147erythro-N-[1-[4-(1-Dodecynyl)-2-thienyl]-3-hydroxy-1-methoxy-2-propyl]-N'-methyl-1,2-benzenedicarboxamide

A solution oferythro-2-[1-[4-(1-dodecynyl)-2-thienyl]-3-hydroxy-1-methoxy-2-propyl]-1H-isoindole-1,3(2H)-dione(2.10 g) in dimethylformamide (20 ml) and 40% aqueous methylamine (10ml) was stirred at room temperature for two hrs. The reaction mixturewas poured into water (200 ml), ammonium chloride was added, and theproduct was extracted with ethyl acetate. The organic extracts weredried over anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed (silica: 5%methanol/dichloromethane). The appropriate fractions were collected andevaporated. The residue was recrystallized from ethyl acetate to give0.6 g (27%) of product, mp 138°-140° C.

ANALYSIS: Calculated for C₂₉ H₄₀ N₂ O₄ S: 67.94% C 7.86% H 5.46% NFound: 67.52% C 7.85% H 5.26% N

EXAMPLE 148erythro-N-[4-(1-Dodecynyl)-2-thienyl]-1-hydroxy-3-(1,1-dimethylethyldimethylsilyloxy)acetamide

A solution of ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-(1,1-dimethylethyldimethylsilyloxy)propionate(18.4 g) and dry tetrahydrofuran (150 ml) was stirred at 0° C., undernitrogen, as lithium borohydride (22.4 ml, 2.0M in tetrahydrofuran) wasadded dropwise. The reaction mixture was stirred under a nitrogenatmosphere for three hrs, heated under reflux for two hrs, and cooled to0° C. Methanol (30 ml), water (30 ml), and acetic acid (5 ml) were addeddropwise. The solution was neutralized with glacial acetic acid andevaporated. The residue was diluted with water (200 ml) and extractedwith ethyl acetate. The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed (silica; 3% methanol/dichloromethane).The appropriate fractions were collected and evaporated. The residue wascrystallized from ethyl acetate to give 7.1 g (42%) of product, mp135°-136° C.

ANALYSIS: Calculated for C₂₇ H₄₇ NO₃ SSi: 65.67% C 9.59% H 2.84% NFound: 66.05% C 9.26% H 2.82% N

EXAMPLE 149 Ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-(1,1-dimethylethyldimethylsilyloxy)propionate

A solution of ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate(15.00 g), imidazole (6.06 g), and dry dimethylformamide (75 ml) wasstirred at room temperature, under nitrogen, as t-butyldimethylsilylchloride (6.44 g) was added. The reaction mixture was stirred at 35° C.under a nitrogen atmosphere overnight. The solution was poured intowater (500 ml) and extracted with ethyl acetate. The combined organicextracts were dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated. The residue was flash chromatographed (silica;4:1 hexane/ethyl acetate). The appropriate fractions were collected andevaporated to give 18.8 g (99%) of product.

ANALYSIS: Calculated for C₂₉ H₄₉ NO₄ SSi: 65.00% C 9.22% H 2.61% NFound: 64.95% C 9.26% H 2.57% N

EXAMPLE 150erythro-N-[1-[4-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]-N'-octylurea

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (3.00 g),dry pyridine (1.05 g), and dry dimethylformamide (50 ml) was stirred at-10° C., under nitrogen, as a solution of octyl isocyanate (1.45 g) indry dimethylformamide (30 ml) was added dropwise. The reaction mixturewas allow to warm to room temperature, with stirring under nitrogen,overnight. The solution was poured into cold water (500 ml), and thesolid was collected and dried under vacuum. Recrystallization from ethylacetate gave 3.6 g (82%) of product, mp 99°-100° C.

ANALYSIS: Calculated for C₂₈ H₄₈ N₂ O₃ S: 68.25% C 9.82% H 5.68% NFound: 68.36% C 9.73% H 5.67% N

EXAMPLE 1511-Octanol-erythro-N-[1-[4-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]carbamate(ester)

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (3.00 g),dry pyridine (1.05 g) and dry dimethylformamide (50 ml) was stirred at-10° C., under nitrogen, as a solution of octyl chloroformate (1.80 g)in dry dimethylformamide (30 ml) was added dropwise. The reactionmixture was allow to warm to room temperature overnight, with stirringunder nitrogen. The solution was poured into water (500 ml), ammoniumchloride solution was added, and the mixture was extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed (silica; 3-4% methanol/dichloromethane). Theappropriate fractions were collected and evaporated. The residue wasrecrystallized from hexane to give 2.6 g (59%) of product, mp 75°-77° C.

ANALYSIS: Calculated for C₂₈ H₄₇ NO₄ S: 68.11% C 9.59% H 2.84% N Found:68.04% C 9.56% H 2.85% N

EXAMPLE 152erythro-N-[1-[4-(1-Dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propyl]octanamide

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (2.50 g),dry pyridine (0.88 g), and dry dimethylformamide (45 ml) was stirred at-10° C., under nitrogen, as a solution of octanoyl chloride (1.27 g) indry dimethylformamide (30 ml) was added dropwise. The reaction mixturewas allow to warm to room temperature overnight, with stirring undernitrogen. The solution was poured into water (500 ml), ammonium chloridewas added, and the mixture was extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was combined with1.1 g of that previously prepared, and was flash chromatographed(silica; 3-4% methanol/dichloromethane). The appropriate fractions werecollected and evaporated. The residue was recrystallized from ethylacetate to give 3.2 g (61%) of product, mp 98°-100° C.

ANALYSIS: Calculated for C₂₇ H₄₅ NO₃ S: 69.93% C 9.78% H 3.02% N Found:69.71% C 9.84% H 3.00% N

EXAMPLE 153 Ethylthreo-5-[4-(1-dodecynyl)-2-thienyl]-2-methyl-4,5-dihydro-4-oxazolecarboxylate

A solution of ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thienyl]-3-hydroxypropionate(12.00 g), triphenylphosphine (8.21 g) and dry tetrahydrofuran (100 ml)was stirred at 0° C., under nitrogen, as a solution of diethylazodicarboxylate (5.45 g) in dry tetrahydrofuran (50 ml) was addeddropwise. The reaction mixture was stirred for three hrs under anitrogen atmosphere as it was allowed to warm to 15° C. and wasevaporated. The reaction was repeated on the same scale under identicalconditions and the residues were combined and flash chromatographed(silica; 3:1 hexane-ethyl acetate). The appropriate fractions werecombined and evaporated to give 10.7 g (47%) of product. A sample waspurified on a chromatotron (silica; 3:1 heptane-ethyl acetate). Theresidue was dissolved in heptane, filtered, and the filtrate wasevaporated and dried under vacuum to give the analytical sample, as anoil.

ANALYSIS: Calculated for C₂₃ H₃₃ NO₃ S: 68.45% C 8.24% H 3.47% N Found:68.36% C 8.42% H 3.19% N

EXAMPLE 154erythro-1,1-dimethylethylethyl-N-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanylcarbamate

A solution oferythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (5.1 g)and di-tert-butyldicarbonate (3.4 g) in dichloromethane (150 ml) werestirred at ambient temperature under nitrogen overnight. Diethyl ether(150 ml) was added, and the reaction mixture was washed with saturatedsodium bicarbonate solution, and sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and the filtrate was evaporated.The residue was recrystallized from heptane:ethyl acetate/1:1 to give4.6 g (70.4%) of product.

ANALYSIS: Calculated for C₂₄ H₃₉ NO₄ S: 65.87% C 8.98% H 3.20% N Found:66.02% C 9.02% H 2.96% N

EXAMPLE 155erythro-5-Amino-4-[5-(1-dodecynyl)-2-thienyl]-2,2-dimethyl-1,3-dioxane

A solution oferythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (5.1 g),2,2-dimethoxypropane (15.6 g), p-toluenesulfonic acid (3.1 g), anddichloromethane (100 ml) was stirred at ambient temperature overnight.Additional 2,2-dimethoxypropane (7.8 g) and p-toluenesulfonic acid (1.5g) were added, and the mixture was stirred for 3.5 hrs. Saturated sodiumbicarbonate solution was added, the mixture was extracted with ethylacetate, and the extracts were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was evaporated. Theresidue was chromatographed twice on silica gel eluting withchloroform:0.5% methanol to give 1.8 g (32.5%) of product, as an oil.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₂ S: 69.98% C 9.34% H 3.71% N Found:69.97% C 9.45% H 3.64% N

EXAMPLE 156erythro-2-Dimethylamino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol

A solution oferythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (5.1 g)and 37% formaldehyde (11.3 ml), and acetonitrile (100 ml) was stirred atambient temperature for 1 hr. Sodium cyanoborohydride (2.8 g) andtetrahydrofuran (40 ml) were added, and the mixture was stirred for 2.5hrs. Water and glacial acetic acid were added gradually until pH 5 wasobtained. The mixture was stirred 30 mins and evaporated. Water wasadded, the pH was adjusted to 10.5 with ammonium hydroxide solution, andthe mixture was extracted with chloroform. The extract was washed withbrine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was chromatographed twice on silicagel, eluting with chloroform/methanol/2N ammonium hydroxidesolution/970:30:2 to 950:50:3. The appropriate fractions were collectedand combined to give 2.3 g (36%) of product, as an oil.

ANALYSIS: Calculated for C₂₁ H₃₅ NO₂ S: 69.00% C 9.65% H 3.83% N Found:69.03% C 9.79% H 3.85% N

EXAMPLE 157trans-erythro-2-Amino-1-[4-(1-dodecenyl)-2-thienyl]-1,3-propanediol

A solution oferythro-N-[1-[4-(dodecenyl)-2-thienyl]-1,3-dihydroxy-2-propyl]acetamide(5.25 g), 2N sodium hydroxide solution (100 ml), and 95% ethanol (75 ml)was stirred at 50° C. overnight. The reaction mixture was cooled to roomtemperature and diluted with sodium bicarbonate solution (300 ml). Themixture was extracted repeatedly with ethyl acetate and the combinedorganic extracts were dried over anhydrous sodium sulfate, filtered, andthe filtrate was evaporated. The residue was flash chromatographed(silica; 90:9:1 dichloromethane/methanol/ammonium hydroxide). Theappropriate fractions were collected and evaporated. The residue wascrystallized from ethyl acetate to give 3.4 g (73%) of product. Theanalytical sample was obtained by flash chromatography (silica; 8-10%methanol/dichloromethane). The appropriate fractions were collected andevaporated. The residue was recrystallized from ethyl acetate to give1.9 g (41%) of product, mp 112°-115° C.

ANALYSIS: Calculated for C₁₉ H₃₃ NO₂ S: 67.21% C 9.80% H 4.13% N Found:66.66% C 9.79% H 4.09% N

EXAMPLE 158erythro-1-[5-(1-Dodecynyl)-2-thienyl]-2-methylamino-1,3-propanediolMaleate

A solution oferythro-1,1-dimethylethyl-N-{1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxypropanyl}-N-methylcarbamate(2.0 g) was dissolved in methanol (40 ml) and chilled under nitrogen.Cold saturated hydrogen chloride in methanol (2 ml) was added, and thereaction vessel was stoppered and stirred for 2 days at ambienttemperature. The reaction mixture was chilled, the pH was adjusted to 12with 2N sodium hydroxide solution, and extracted with chloroform and 3:1chloroform/isopropanol. The extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was combined with the residues from similarreactions carried out on a 3.3 mmol scale, and the combined material wasflash chromatographed twice on silica gel eluting withchloroform/methanol/2N ammonium hydroxide solution/960:40:3. Theappropriate fractions were collected and evaporated. The residue wastreated with maleic acid in ethyl acetate, and the maleate wasrecrystallized from cyclohexane to give 1.6 g (44.7%) of product, mp78°-80° C.

ANALYSIS: Calculated for C₂₀ H₃₃ NO₂ S.C₄ H₄ O₄ : 61.64% C 7.98% H 3.00%N Found: 61.40% C 8.17% H 2.90% N

EXAMPLE 159 Ethyl trans-3-[3-(1-Dodecynyl)phenyl]-2-propenoate

To a solution of 3-(1-dodecynyl)benzaldehyde (23.0 g) in toluene (150ml) was added carbethoxymethylenetriphenylphosphorane (35.5 g) in oneportion. The mixture was warmed at 80° C. for 5 hr, allowed to cool toroom temperature, and concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with ethyl acetate/hexane/1:15).The appropriate fractions were collected and evaporated to afford 21.1 g(73%) of product.

ANALYSIS: Calculated for C₂₃ H₃₂ O₂ : 81.13% C 9.47% H Found: 81.25% C9.45% H

EXAMPLE 160 (2S-Trans-3-[3-(1-Dodecynyl)phenyl]oxiranemethanol

To a slurry of 4A molecular sieves (1 g) in dry dichloromethane (50 ml)was added a solution of (+) diisopropyltartrate (524 mg) in drydichloromethane (10 ml). The mixture was cooled to -20° C. andtitanium(IV) isopropoxide (0.53 ml) was added, followed bytert-butyl-hydroperoxide (3.0M, isooctane) (20 ml). The mixture wasstirred for 20 mins at -20° C. and a solutiontrans-3-[3-(1-dodecynyl)phenyl]propen-1-ol (8.88 g) in drydichloromethane (20 ml) was added slowly by means of syringe. Themixture was stirred for 30 mins at -20° C. and 25% aqueous sodiumhydroxide solution (6 ml) and water (40 ml) were added. The mixture wasallowed to warm to room temperature and stirred for 30 mins. The organicphase was separated and the aqueous phase was extracted withdichloromethane. The organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over silica gel (eluted with ethylacetate/hexane/1:3). The appropriate fractions were collected andevaporated. Crystallization of the residue from hexane afforded 5.61 g(60%) of product, mp 41°-42° C., [α]_(D) ²⁵ -31.7 (c. 1.04, chloroform).

ANALYSIS: Calculated for C₂₁ H₃₀ O₂ : 80.21% C 9.62% H Found: 80.25% C9.49% H

EXAMPLE 161 (2S-trans)-3-[3-(1-Dodecynyl)phenyl]epoxypropyl BenzoylCarbamate

To a solution of (2S-trans)-3-[3-(1-dodecynyl)phenyl]oxiranemethanol(63.1 g) in dry dichloromethane (60 ml) was added a solution of benzoylisocyanate (3.23 g) in dichloromethane (20 ml). The mixture was stirredfor 2 hr at room temperature, diluted with dichloromethane and washedwith water. The organic phase was separated, dried over anhydrousmagnesium sulfate, and concentrated in vacuo. The residue waschromatographed over silica gel (eluted with ethyl acetate/heptane/1:1).The appropriate fractions were collected and concentrated to afford 9.23g (99%) of product, [α]_(D) ²⁵ -31.8° (c. 0.78, chloroform).

ANALYSIS: Calculated for C₂₉ H₃₅ NO₄ : 75.46% C 7.64% H 3.03% N Found:75.10% C 7.62% H 3.14% N

EXAMPLE 162(2'S,4R)-4-{[3-(1-Dodecynyl)phenyl]-2'-hydroxymethyl}-2-oxazolidinone

To a solution of (2S-trans)-3-[3-(1-dodecynyl)phenyl]epoxypropylbenzoylcarbamate (8.65 g) in tetrahydrofuran (60 ml) was added sodiumhydride (215 mg). The mixture was heated under reflux for 30 mins,allowed to cool to room temperature and quenched with 25% aqueous sodiumhydroxide solution (8 ml). The mixture was dissolved in ethyl acetate,and the organic phase was washed with water and brine. The organic phasewas separated, dried over anhydrous magnesium sulfate, and concentratedin vacuo. The residue was flash chromatographed twice over silica gel(eluted with ethyl acetate/hexane/3:2). The appropriate fractions werecollected and evaporated afford 5.10 g (76%) of product, mp 85°-86° C.;[α]_(D) ²⁵ =+7.4° (c. 0.86 chloroform).

ANALYSIS: Calculated for C₂₂ H₃₁ NO₃ : 73.92% C 8.74% H 3.92% N Found:74.08% C 9.03% H 3.80% N

EXAMPLE 163 (2R,3S)-2-Amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediolAcetate

To a solution of(2'S,4R)-4-{[3-(1-dodecynyl)phenyl]-2'-hydroxymethyl}-2'-2-oxazolidone(5.20 g) in ethanol (20 ml) was added 25% aqueous sodium hydroxide (15ml). The mixture was heated under reflux for 3 hr, allowed to cool toroom temperature and stirred overnight. The mixture was diluted withethyl acetate, and water was added. The aqueous phase was extracted withethyl acetate. The organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over silica gel (eluted withchloroform/methanol/9:1 followed by chloroform:methanol/5:1). Theappropriate fractions were collected and evaporated to afford 3.9 g(87%) of (2R,3S)-2-amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediol.

To a solution of the amine in ethyl acetate (10 ml) was added glacialacetic acid (1 ml). The mixture was stirred for 15 mins at roomtemperature and concentrated in vacuo, then under high vacuum. Theresidue was crystallized twice from ethyl acetate to afford 1.75 g (29%overall) of product, mp 104°-105° C., [α]_(D) ²⁵ =+16.8° (c. 0.5ethanol).

ANALYSIS: Calculated for C₂₃ H₃₇ O: 70.55% C 9.52% H 3.58% N Found:70.33% C 9.50% H 3.54% N

EXAMPLE 164 (2R-trans)-3-[3-(1-Dodecynyl)phenyl]oxiranemethanol

To a solution (-) diisopropyltartrate (524 mg) in dry dichloromethane(60 ml) and 4A molecular sieves (1 g) at -20° C. was added titanium(IV)isopropoxide (0.53 ml) followed by t-butylhydroperoxide (3.0M,isooctane) (20 ml). The reaction mixture was stirred for 20 mins at -20°C. and then a solution of trans-3-[3-(1-dodecynyl)phenyl]propene-1-ol(8.88 g) in dichloromethane (20 ml) was added slowly. The mixture wasstirred for 1.5 hr and quenched with 25% aqueous sodium hydroxide (6 ml)followed by water (40 ml). The mixture was allowed to warm to roomtemperature, and was stirred for 30 min. The organic phase wasseparated, and the aqueous phase was extracted with dichloromethane. Theorganic extracts were combined, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated in vacuo. The residue waschromatographed over silica gel (eluted with ethyl acetate/Heptane/1:2).The appropriate fractions were collected and evaporated. The residue wascrystallized from heptane to afford 6.5 g (69%) of product, mp 41°-42°C. [α]_(D) ²⁵ +33.1° (c. 0.725, chloroform).

ANALYSIS: Calculated for C₂₁ H₃₀ O₂ : 80.21% C 9.62% H Found: 80.37% C9.49% H

EXAMPLE 165 (2R-trans))-3-[3-(1-Dodecynyl)phenyl]epoxypropyl BenzoylCarbamate

To a solution of (2R-trans)-3-[3-(1-dodecynyl)phenyl]oxiranemethanol(11.8 g) and dichloromethane (100 ml) at room temperature was added asolution of benzoyl isocyanate (5.7 g) in dichloromethane (30 ml). Thereaction mixture was stirred at room temperature for 30 mins, dilutedwith dichloromethane (300 ml), and the solution was washed with water.The organic phase was separated, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated in vacuo. The residue waschromatographed over silica gel (eluted with ethyl acetate:Heptane/1:1)to afford 17.5 g (99%) of the product, as an oil, [α]_(D) ²⁵ +34.4° (c.0.85, chloroform).

ANALYSIS: Calculated for C₂₉ H₃₅ NO₄ : 75.46% C 7.64% H 3.03% N Found:75.29% C 7.50% H 2.82% N

EXAMPLE 166(2'R,4S)-4-{[3-(1-Dodecynyl)phenyl]-2'-hydroxymethyl}-2-oxazolidinone

To a solution of (2R-trans)-3-[3-(1-dodecynyl)phenyl]epoxypropyl benzoylcarbamate (16.0 g) and tetrahydrofuran (150 ml) at room temperature wasadded sodium hydride (400 mg) in one portion. The mixture was heatedunder reflux for 1.5 hr, allowed to cool to room temperature, and 25%aqueous sodium hydroxide (20 ml) was added over 30 mins, with stirring.The slurry was diluted with ethyl acetate, and the mixture was washedwith water and brine. The organic phase was separated, dried overanhydrous magnesium sulfate, filtered, and the filtrate was concentratedin vacuo. The residue was flash chromatographed over silica gel (elutedwith ethyl acetate/Heptane/2:1). The appropriate fractions werecollected and concentrated to afford 9.90 g (80%) of product, mp84.5°-86° C., [α]_(D) ²⁵ -6.8° (c. 0.845, chloroform).

ANALYSIS: Calculated for C₂₂ H₃₁ NO₃ : 73.92% C 8.74% H 3.92% N Found:73.59% C 8.77% H 3.82% N

EXAMPLE 167 (2S,3R)-2-Amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediolAcetate

To a solution of(2R-trans)-4-{[3-(1-dodecynyl)phenyl]-2'-hydroxymethyl}-2-oxazolidinone(5.4 g) in ethanol (40 ml) was added 25% aqueous sodium hydroxidesolution (15 ml). The reaction mixture was heated at 80° C. for 4 hr,and then allowed to cool to room temperature. The solution waspartitioned between ethyl acetate and water. The organic phase wasseparated, and the aqueous phase was extracted with ethyl acetate. Theorganic phases were combined, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated in vacuo. The residue wasflash chromatographed over silica gel (eluted withchloroform/methanol/9:1 followed by chloroform:methanol/5:1). Theappropriate fractions were collected and concentrated to afford 3.24 gof (2S,3R)-2-amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediol.

To a solution of the amine in ethyl acetate (10 ml) was added glacialacetic acid (0.80 ml). The mixture was stirred for 10 min at roomtemperature and concentrated in vacuo. The residue was crystallizedtwice from ethyl acetate to afford 2.35 g (40% for two steps) ofproduct, mp 104°-105° C. [α]_(D) ²⁵ =-17.3° (c. 0.53, ethanol).

ANALYSIS: Calculated for C₂₃ H₃₇ NO₄ : 70.55% C 9.52% H 3.58% N Found:70.62% C 9.54% H 3.55% N

EXAMPLE 168(2S,3S)-2-Amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol Acetate

To a solution of(2S,3S)-1,1-dimethylethyl)-N-(1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanoyl)carbamate(1.77 g) and methanol (20 ml) was added ethanolic hydrogen chloride (5ml). The reaction mixture was stirred at room temperature for 24 hrs,diluted with ethyl acetate, and washed with 25% aqueous sodium hydroxidesolution. The aqueous phase was extracted with ethyl acetate, and theorganic phases were combined, dried over magnesium sulfate, filtered,and the filtrate was concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with chloroform/methanol/7:1) toafford 630 mg (46%) of product as the free base. To a solution of theproduct free base in ethyl acetate (5 ml) was added glacial acetic acid(0.11 ml). The mixture was cooled to 0° C. The acetate salt crystallizedto give 522 mg (70%) of product.

The reaction was repeated on a similar scale to afford 763 mg (40%) ofthe acetate. The products from the reactions were combined andcrystallized from ethyl acetate to give 961 mg of product, mp 114°-118°C., [α]_(D) ²⁵ =+7° (c. 0.63, ethanol).

ANALYSIS: Calculated for C₂₁ H₃₅ NO₄ S: 63.44% C 8.87% H 3.52% N Found:63.16% C 9.22% H 3.56% N

EXAMPLE 169(2S,3S)-1,1-dimethylethyl-N-(1-[5-(1-dodecynyl)-2-thienyl]-1,3-dihydroxy-2-propanylcarbamate

To a solution of(2S,4S)-1,1-dimethylethyl-4-{[5-(1-dodecynyl)-2-thienyl]-2-hydroxymethyl}-1,2-dimethyl-3-oxazolidinecarboxylate(7.50 g) in methanol (70 ml) was added p-toluenesulfonic acid (1.5 g).The mixture was stirred at room temperature for 1 hr, diluted with ethylacetate, and washed with water. The aqueous phase was extracted withethyl acetate, and the organic phases were combined, dried overanhydrous magnesium sulfate, filtered, and the filtrate was concentratedin vacuo. The residue was recrystallized twice from ethylacetate:heptane/1:2 to afford 5.25 g of product, mp 74°-75° C.; [α]_(D)²⁵ =+12.7° (c. 0.74, chloroform).

ANALYSIS: Calculated for C₂₄ H₃₉ NO₄ S: 65.87% C 8.98% H 3.20% N Found:65.98% C 9.01% H 3.19% N

EXAMPLE 170(2S,4S)-1,1-Dimethylethyl-4-{(5-(1-dodecynyl)-2-thienyl]-2-hydroxymethyl}-2,2-dimethyl-3-oxazolidinecarboxylate

To a solution of 2-(1-dodecynyl)thiophene (23.4 g) in tetrahydrofuran(150 ml) at -78° C. was added n-butyllithium (1.52M in hexanes) dropwiseby means of an addition funnel. The mixture was stirred for 1.5 hrs at-78° C., and a solution of1,1-dimethylethyl-(S)-4-formyl-2,2-dimethyl-3-oxazolidnecarboxylate(14.4 g) in tetrahydrofuran (30 ml) was added slowly. The mixture wasstirred for 1 hr, diluted with ethyl acetate, and washed with water. Theaqueous phase was extracted with ethyl acetate. The organic phases werecombined, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with ethyl acetate:heptane/1:7)to afford 22.3 g (74%) of a mixture of diastereomers (4:1/erythro:threo)of product.

To a solution of 22.3 g of the mixture of diastereomers of product intetrahydrofuran (100 ml) was added acetic anhydride (26.7 ml) followedby triethylamine (54 ml) and 4-dimethylaminopyridine (2.7 g). Themixture was stirred for 2 hr at room temperature, diluted with ethylacetate, and washed with water. The aqueous phase was extracted withethyl acetate, the organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over silica gel (eluted with ethylacetate:heptane/1:14). The appropriate fractions were collected andevaporated to afford 13.4 g (55%) of the pure erythro1,1-dimethyl-4-{[5-(1-dodecynyl)-2-thienyl]acetoxymethyl}-2,2-dimethyl-3-oxazolidincarboxylateand 6.2 g (26%) of a mixture of erythro- and threo- isomers.

To a solution of the erythro isomer (13.4 g) in methanol (70 ml) wasadded potassium carbonate (10.6 g) in one portion. The mixture wasstirred for 20 min at room temperature, filtered, and the filter cakewas washed with ethyl acetate. The filtrate was concentrated to 1/3 ofits original volume, diluted with ethyl acetate, and washed with water.The aqueous phase was extracted with ethyl acetate, and the organicphases were combined, dried over magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo to afford 10.34 g (84%) of product,[α]_(D) ²⁵ =+1° (c. 1.15, chloroform.

ANALYSIS: Calculated for C₂₇ H₄₃ NO₄ S: 67.89% C 9.07% H 2.93% N Found:68.21% C 9.05% H 2.39% N

EXAMPLE 171(4S)-3-{(2'S,3'R)-2'-Bromo-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone

To a slurry of (4S)-3-(bromoacetyl)-4-(phenylmethyl)-2-oxazolidinone(11.3 g) in diethyl ether (90 ml) at -78° C. was added di-n-butylborontriflate (10.5 ml) followed by triethylamine (7.5 ml). The mixture wasstirred for 5 min at -78° C., allowed to warm to room temperature, andstirred for 2 hrs. The bi-phasic solution was gradually cooled to -78°C., and 4-(1-dodecynyl)-2-thiophenecarboxaldehyde (11.5 g) was added bymeans of a syringe. The mixture was stirred for 20 mins at -78° C.,allowed to warm to 0° C., and stirred for an additional 2 hrs. Themixture was diluted with diethyl ether and washed with 1N aqueous sodiumbisulfate solution followed by water. The organic phase was separatedand concentrated in vacuo. The residue was diluted with diethyl ether(90 ml) and cooled to 0° C. To the solution was added 1:1/30% aqueoushydrogen peroxide/methanol (90 ml). The mixture was stirred at 0° C. for1 hr, and poured into saturated sodium bicarbonate solution (100 ml).The aqueous phase was extracted with diethyl ether, the organic phaseswere combined, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with ethyl acetate/heptane/1:15followed by increasing polarity to ethyl acetate/:heptane/1:5). Theappropriate fractions were collected and evaporated to afford 12.6 g(58%) of productl; [α]_(D) ²⁵ =+41.3° (c. 1.47, chloroform).

ANALYSIS: Calculated for C₂₉ H₃₆ BrNO₄ S: 60.62% C 6.32% H 2.44% NFound: 60.78% C 6.62% H 2.58% N

EXAMPLE 172(4S)-3-{2'R,3'S)-2'-Azido-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone

To a solution of(4S)-3-{2'S,3'R)-2'-bromo-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone(20.4 g) and dimethylsulfoxide (150 ml) was added (4.61 g) sodium azidein one portion. The reaction mixture was stirred at room temperature for5 hrs, diluted with heptane/dichloromethane/2:1 (3 l), and washed withwater. The organic phase was separated, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was flash chromatographed over silica gel (eluted with ethylacetate/heptane/1:2). The appropriate fractions were collected andevaporated to afford 15.4 g (81%) of product. A 1.5 g-portion wasrechromatographed over silica gel (eluted with chloroform) to afford theanalytical sample as a yellow oil, [α]_(D) ²⁵ =+15.4° (c. 1.48,chloroform).

ANALYSIS: Calculated for C₂₉ H₃₆ N₄ O₄ S: 64.90% C 6.76% H 10.44% NFound: 64.61% C 6.87% N 10.06% N

EXAMPLE 173 Methyl(2R,3S)-2-Azido-3-hydroxy-3-[4-(1-dodecynyl)-2-thienyl]propionate

To a solution of(4S)-3-{(2'R,3'S)-2'-azido-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone(13.2 g) in methanol/dichloromethane/1:1 at 0° C. was added a solutionof methoxymagnesium bromide, prepared by the addition of methylmagnesiumbromide (3.0M, diethyl ether) (9.0 ml) to methanol (35 ml). The solutionwas stirred for 20 min at 0° C., and 1N sodium bisulfate solution wasadded. The solution was partitioned between dichloromethane (500 ml) andwater (200 ml). The aqueous phase was separated and extracted withdichloromethane. The organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over 400 g of silica gel (elutedwith ethyl acetate/heptane/1:6). The appropriate fractions werecollected and evaporated. A 1.07 g-sample of the residue wasrechromatographed over silica gel (100 g) (eluted with chloroform) toafford 0.93 g (65%) of product, as an oil.

ANALYSIS: Calculated for C₂₀ H₂₉ N₃ O₃ S: 61.35% C 7.47% H 10.73% NFound: 61.26% C 7.32% H 10.17% N

EXAMPLE 174(2S,3S)-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol Maleate

To a solution of methyl(2R,3S)-2-azido-3-hydroxy-3-[4-(1-dodecynyl)-2-thienyl]propionate (5.50g) and diethyl ether (100 ml) at 0° C. was added lithium aluminumhydride (1.74 g) in small portions. The mixture was stirred at 0° C. for1 hr, allowed to warm to room temperature and stirred for 2 hrs. Thesolution was cooled to 0° C., and ethyl acetate was added. Thesuspension was diluted with ethyl acetate (700 ml) and washed with water(200 ml). The aqueous phase was extracted with ethyl acetate, and theorganic phases were combined, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated in vacuo. The residue wasflash chromatographed over silica gel (eluted withchloroform/methanol/1:1). The appropriate fractions were collected andevaporated. The residue was crystallized from ethyl acetate/heptane/1:4to afford 2.15 g (45%) of product free base, [α]_(D) ²⁵ =-16.3 (c. 0.69,chloroform). The N-t-butylcarbamate was prepared fromdi-tert-butyldicarbonate in methylene chloride according to theprocedure of Example 154 and was optically pure by chiral high pressureliquid chromatographic analysis. A second reaction yielded 1.05 g ofproduct free base, [α]_(D) ²⁵ =-17.1° (c. 0.52, chloroform).

To a solution of 2.78 g of product free base in ethyl acetate (50 ml)was added maleic acid (1.16 g). The precipitate was recrystallized twotimes from ethyl acetate to afford 3.26 g (87%) of product, mp 121°-122°C., [α]_(D) ²⁵ =-18.0° (c. 0.54, ethanol).

ANALYSIS: Calculated for C₂₃ H₃₅ NO₆ S: 60.90% C 7.78% H 3.09% N Found:60.66% C 7.87% H 2.99% N

EXAMPLE 175(4R)-3-{2'R,3'S)-2'-Bromo-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone

To a solution of 4(R)-3(bromoacetyl)-2-oxazolidinone (22.6 g) in diethylether (180 ml) at -78° C. was added di-n-butylboron triflate (21 ml)followed by triethylamine (15 ml). The reaction mixture was stirred for5 min at -78° C., allowed to warm to room temperature, and stirred for2.5 hrs. The mixture was gradually cooled to -78° C. and4-(1-dodecynyl)-2-thiophene carboxaldehyde (23 g) was added slowly bymeans of a syringe. The mixture was stirred at -78° C. for 20 min,allowed to warm to 0° C., and stirred for 2.5 hrs. The mixture wasdiluted with diethyl ether (700 ml), and the solution was washed 1Nsodium bisulfate solution (two times with 300 ml) followed by water (300ml). The organic phase was separated and concentrated in vacuo. Theresidue was dissolved in diethyl ether (100 ml) and cooled to 0° C. Tothe resulting solution was added 30% hydrogen peroxide/methanol/1:1 (180ml). The solution was stirred for 1 hr and poured into saturated sodiumbicarbonate solution (300 ml). The aqueous phase was extracted withethyl acetate. The organic phases were combined, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over silica gel (eluted with ethylacetate/heptane/1:12 followed by ethyl acetate/heptane/1:5). Theappropriate fractions were collected and evaporated. A 1.0 g-sample ofthe residue was rechromatographed over silica gel (eluted withchloroform) to afford 0.93 g (47%) of product, as an oil.

ANALYSIS: Calculated for C₂₉ H₃₆ O₄ BrSN: 60.62% C 6.31% H 2.43% NFound: 60.42% C 6.43% H 2.52% N

EXAMPLE 176(4R)-3-{2'S,3'R)-2'-Azido-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone

To a solution of(4R)-3-{2'S,3'R)-2'-azido-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone(15.0 g) in dimethylsulfoxide (120 ml) was added sodium azide (3.4 g).The reaction mixture was stirred at room temperature for 6 hrs, dilutedwith a solution of heptane/dichloromethane/2:1 (3 l), and washed withwater. The organic phase was separated, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresidue was flash chromatographed over silica gel (eluted with ethylacetate/heptane/1:2). The appropriate fractions were collected andevaporated. A 1.00 g-sample of the residue was rechromatographed oversilica gel (eluted with chloroform) to afford 800 mg (71%) of product,[α]_(D) ²⁵ =17.3° (c. 0.48, chloroform).

ANALYSIS: Calculated for C₂₉ H₃₆ N₄ O₄ S: 64.90% C 6.76% H 10.44% NFound: 65.45% C 6.86% H 9.98% N

EXAMPLE 177(2R,3R)-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol Maleate

To a solution of(4R)-3-{2'S,3'R)-2'-azido-3'-hydroxy-3'-[4-(1-dodecynyl)-2-thienyl]propanoyl}-4-(phenylmethyl)-2-oxazolidinone(11.4 g) and dichloromethane:methanol/1:1 (140 ml) at 0° C. was added aslurry of methoxymagnesium bromide, prepared by the addition ofmethylmagnesium bromide (3.0M, diethyl ether (7.8 ml) to methanol (35ml). The mixture was stirred for 20 mins, at 0° C. and quenched with 1Naqueous sodium bisulfate solution (50 ml). The mixture was partitionedbetween dichloromethane (500 ml) and water (100 ml). The aqueous phasewas extracted with dichloromethane and the organic phases were combined,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was flash chromatographed over silicagel (eluted with ethyl acetate:heptane/1:5). The appropriate fractionswere collected and evaporated to afford 5.38 g (65%) of methyl(2S,3R)-2-azido-3-hydroxy-3-[4-(1-dodecynyl)-2-thienyl]propionate.

To a solution of(2S,3R)-2-azido-3-hydroxy-3-[4-(1-dodecynyl)-2-thienyl]propionate (5.38g) and diethyl ether (100 ml) at 0° C. was added lithium aluminumhydride (1.70 g) in small portions. The mixture was stirred for 30 minsat 0° C., allowed to warm to room temperature, and stirred for 2 hrs.The mixture was cooled to 0° C., and ethyl acetate was added. Themixture was partitioned between water (100 ml) and ethyl acetate (700ml). The emulsion was extracted with ethyl acetate, and the organicphases were combined, dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated in vacuo. The residue was flashchromatographed over silica gel (eluted with chloroform/methanol/7:1followed by chloroform/methanol/5:1). The appropriate fractions werecollected and evaporated to afford 2.25 g (49%) of product free base,[α]_(D) ²⁵ =+17.2° (c. 0.54, chloroform).

A small sample of the N-t-butylcarbamate derivative was prepared as inExample 154 and was optically pure by chiral high pressure liquidchromatography analysis.

To a solution of product free base (1.47 g) in ethyl acetate (50 ml) wasadded maleic acid (615 mg). The precipitate was recrystallized to afford1.88 g (95%) of product, mp 121°-122° C., [α]_(D) ²⁵ =+18.9° (c. 0.57,ethanol).

ANALYSIS: Calculated for C₂₃ H₃₅ NO₆ S: 60.90% C 7.78% H 3.09% N Found:60.84% C 7.77% H 3.04% N

EXAMPLE 178 trans-3-[3-(1-Dodecynyl)phenyl]propen-1-ol

To a solution of ethyl trans-3-[3-(1-dodecynyl)phenyl]-2-propenoate(10.0 g) and dry tetrahydrofuran (100 ml) at -78° C. was addeddiisobutylaluminum hydride (1.5M in toluene) (49 ml) slowly. Thereaction mixture was stirred for 20 mins at -78° C., and 25% sodiumhydroxide solution (3 ml) was added. The mixture was slowly warmed toroom temperature and an additional 25% sodium hydroxide solution (3 ml)was added. The mixture was diluted with ethyl acetate and washed withwater and brine. The organic phase was separated, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated in vacuo.The residue was flash chromatographed over silica gel (eluted with ethylacetate/hexane/1:3). The appropriate fractions were collected andevaporated to afford 7.14 g (81%) of product.

ANALYSIS: Calculated for C₂₁ H₃₀ O: 84.51% C 10.13% H Found: 84.43% C10.23% H

EXAMPLE 179 2-(1-Dodecynyl)thiophene

To a solution of 2-iodothiophene (31.5 g), 1-dodecyne (2.5 g),triethylamine (105 ml), and tetrahydrofuran (100 ml) was added(bis)triphenylphosphine palladium(II)chloride (1.73 g) followed bycopper(I)iodide (0.24 g). The reaction mixture was warmed to 55° C. andstirred for 7 hr. The solution was allowed to cool to room temperatureand stirred overnight. The mixture was filtered, and the precipitate waswashed with ethyl acetate. The filtrate was diluted with ethyl acetateand washed with water and brine. The organic phase was separated, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was flash chromatographed over silicagel (elated with hexane). The appropriate fractions were collected andevaporated. The residue was distilled to afford 27.6 g (74%) of product,bp 145°-150° C. at 0.7 mm Hg.

ANALYSIS: Calculated for C₁₆ H₂₄ S: 77.36% C 9.74% H Found: 77.25% C9.69% H

EXAMPLE 180 2-(1-Dodecynyl)fluorobenzene

To a solution of 2-bromofluorobenzene (49 g), 1-dodecyne (210 ml)triethylamine (210 ml), and tetrahydrofuran (50 ml) was added(bis)triphenylphosphine palladium(lI)chloride (532 mg) andcopper(I)iodide (532 mg). The reaction mixture was warmed to 55° C. andstirred for 24 hr. The mixture was allowed to cool to room temperatureand filtered. The precipitate was washed with ethyl acetate, and thefiltrate was diluted with ethyl acetate and washed with water and brine.The organic phase was separated, dried over anhydrous magnesium sulfate,filtered and the filtrate was concentrated in vacuo. The residue wasflash chromatographed over silica gel (eluted with hexane). Theappropriate fractions were collected and evaporated. The residue wasdistilled to afford 11 g (15%) of product, bp 175°-180° C. at 1 mm Hg.

ANALYSIS: Calculated for C₁₈ H₂₅ F: 83.03% C 9.68% H Found: 83.11% C9.80% H

EXAMPLE 181 2-(1-Undecynyl)fluorobenzene

To a solution of 2-bromofluorobenzene (17.5 g), 1-undecyne (18.3 g),tetrahydrofuran (50 ml), and triethylamine (70 ml) was addedbistriphenylphosphine palladium(II)chloride (1.2 g) and copper(I) iodide(162 mg). The reaction mixture was stirred at 55° C. for 3 hr, and anadditional 2-bromofluorobenzene (2.0 g) and bistriphenylphosphinepalladium(II)chloride (200 mg) were added. The mixture was stirred at55° C. overnight, allowed to cool to room temperature, diluted withethyl acetate and washed with water. The organic phase was dried overanhydrous magnesium sulfate, filtered, and the filtrate was concentratedin vacuo. The residue was chromatographed over silica gel (eluted withhexane). The appropriate fractions were collected and evaporated. Theresidue was distilled twice under vacuum to give 13.1 g (53%) ofproduct.

ANALYSIS: Calculated for C₁₇ H₂₃ F: 82.88% C 9.41% H Found: 83.11% C9.81% H

EXAMPLE 182 2-Fluoro-3-(1-undecynyl)benzaldehyde

To a solution of 2-(1-undecynyl)fluorobenzene (7.00 g) andtetrahydrofuran (70 ml) was added slowly n-butyllithium (1.6M, 17.8 ml)at -78° C. The reaction mixture was stirred at -78° C. for 1.5 hrs.Dimethylformamide (2.28 ml) was added slowly, and the solution wasallowed to warm to room temperature over 1 hr, with stirring. Methylenechloride (300 ml) was added, and the solution was washed with 50%hydrochloric acid. The aqueous phase was extracted with methylenechloride. The extracts were combined, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica (250 g), eluting with hexane followed by ethylacetate/hexane (1:4). The appropriate fractions were collected andevaporated to provide 3.53 g (45.2%) of product as an oil.

EXAMPLE 183erythro-2-Amino-1-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]-1,3-propanediolMaleate

A solution oferythro-N-{1,3-dihydroxy-1-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]-2-propanyl}acetamide(4.3 g), 2N sodium hydroxide (40 ml), and ethanol (25 ml) were heated at60° C., under nitrogen, for 23 hrs. The reaction mixture was cooled andextracted with chloroform. The extract was washed with sodium chloridesolution, dried over anhydrous magnesium, sulfate, filtered, and thefiltrate was evaporated. The residue was chromatographed three times onsilica gel eluting with chloroform:methanol:2N ammoniumhydroxide/950:50:3. The appropriate fractions were combined, evaporatedand the residue was dried each time to give 1.7 g (46% yield) of productfree base. Maleic acid (0.6 g) in ethyl acetate was added to the productfree base. The precipitate was collected and recrystallized from ethylacetate to give which gave 1.10 g (22% yield) of product, mp 142°-143°C.

Analysis: Calculated for C₂₅ H₃₀ N₂ O₆ : 66.06% C 6.65% H 6.16% N Found:66.07% C 6.76% H 6.12% N

EXAMPLE 184erythro-N-{1,3-Diacetyloxy-1-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]-2-propanyl}acetamide

A mixture ofN-{1,3-dihydroxy-1-[6-(7-phenyl-1-heptynyl)-2-pyridinyl]-2-propanyl}acetamide(9.4 g), acetic anhydride (14.5 ml), triethylamine (32 ml), and4-dimethylaminopyridine (0.31 g), and tetrahydrofuran (140 ml) wasstirred at room temperature overnight. The reaction mixture wasevaporated, methanol was added to the residue, and the solution waswarmed at 50° C. for 20 min. The mixture was evaporated and azeotropedwith toluene. A solution of 7.5% sodium bicarbonate was added to theresidue until pH 8.5, and the mixture was extracted with chloroform. Theextract was dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was chromatographed on silica geleluting with chloroform:2-propanol (0.5% to 1%). The appropriatefractions were collected and evaporated to give 9.8 g (85% yield) ofproduct. Portions were rechromatographed twice, eluting withhexane:chloroform:2-propanol to give the analytical sample, as an oil.

Analysis: Calculated for C₂₇ H₃₂ N₂ O₅ : 69.81% C 6.94% N 6.03% N Found:69.56% C 7.05% H 5.93% N

EXAMPLE 185erythro-2-Amino-1-[6-(1-decynyl)-2-pyridinyl]-l,3-propanediol Maleate

A solution oferythro-N-{1-[6-(1-decynyl)-2-pyridinyl]-1,3-dihydroxy-2-propanyl}acetamide(3.0 g), 2N sodium hydroxide (45 ml), and ethanol (45 ml) was heated at100° C., under nitrogen, for 4 hrs. The reaction mixture was cooled,water was added, and the mixture was extracted withchloroform:2-propanol/3:1. The combined extracts were washed with sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was chromatographed twice onsilica gel, eluting with chloroform:methanol:2N ammonium hydroxidesolution/960:40:3. The appropriate fractions were collected andevaporated each time to give 0.93 g (35%) of product free base, as anoil. A 0.76 g-portion of product free base was treated with maleic acid(0.29 g) in ethyl acetate to give 0.50 g of the analytical sample ofproduct, mp 126°-128° C.

Analysis: Calculated for C₂₂ H₃₂ N₂ O₆ : 62.84% C 7.67% H 6.66% N Found:62.58% C 7.72% H 6.84% N

EXAMPLE 186erythro-2-Amino-1-[4-(1-dodecynyl)-2-thiazolyl]-1,3-propanediolHydrochloride

A solution oferythro-N-{1-[4-(1-dodecynyl)-2-thiazolyl]-1,3-dihydroxy-2-propanyl}acetamide(5.8 g), 2N sodium hydroxide solution (39 ml) and ethanol (25 ml) washeated at 60° C., under nitrogen, for 23 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with brine solution, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was evaporated. Theresidue was chromatographed on silica gel eluting withchloroform:methanol:2N ammonium hydroxide solution/950:50:3. Theappropriate fractions were collected and concentrated. A 2.4 g-portionof the residue (4.3 g) was dissolved in ethyl acetate, concentratedhydrochloric acid (0.6 ml) was added, and the mixture was evaporated.The residue was redissolved and evaporated with ethyl acetate and then2-propanol. The residue was dried under vacuum to give 2.4 g (76.0%) ofproduct, mp 194°-197° C.

Analysis: Calculated for C₁₈ H₃₀ N₂ O₂ S.HCl: 57.66% C 8.33% H 7.47% NFound: 57.35% C 8.48% H 7.25% N

EXAMPLE 187 Ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thiazolyl]-3-hydroxypropionate

A solution of 4-(1-dodecynyl)-2-thiazolecarboxaldehyde (18.3 g),acetamidomalonic acid monoethyl ester (14.1 g), and triethylamine (8.3g) in dry tetrahydrofuran (70 ml) was stirred, under nitrogen, for 4hrs. The precipitate was collected, the filter cake washed with heptane,and recrystallized from ethyl acetate to give 16.0 g (57.0%) of product,mp 131°-132.5° C.

Analysis: Calculated for C₂₂ H₃₄ N₂ O₄ S: 62.53% C 8.11% H 6.63% NFound: 62.36% C 8.28% H 6.58% N

EXAMPLE 188erythro-N-{1-[4-(1-Dodecynyl)-2-thiazolyl]-1,3-dihydroxy-2-propanyl}acetamide

To a solution of ethylerythro-2-acetamido-3-[4-(1-dodecynyl)-2-thiazolyl]-3-hydroxypropionate(13.8 g) in dry tetrahydrofuran (275 ml) was added slowly 2M lithiumborohydride/tetrahydrofuran (14 ml) at 5° C., under nitrogen, and themixture was stirred at room temperature over the weekend. The reactionmixture was chilled, and methanol:water/1:1 was added slowly, followedby glacial acetic acid (1.8 ml) in methanol:water/1:1 (25 ml). Thesolution was stirred at room temperature for 1 hr, evaporated, and thenazeotroped with methanol. Ethyl acetate was added to the residue,saturated sodium bicarbonate solution was added until pH 8, and themixture was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was flash chromatographed onsilica gel eluting with ethyl acetate to ethyl acetate:0.5% methanol.The appropriate fractions were collected and evaporated. An 8.0g-portion of the residue (11.1 g) was recrystallized from ethyl acetateto give 6.90 g (77.0% yield) of product, mp 93°-95° C.

Analysis: Calculated for C₂₀ H₃₂ N₂ O₃ S: 63.12% C 8.48% H 7.36% NFound: 63.26% C 8.82% H 7.30% N

EXAMPLE 189erythro-2-Amino-1-[4-(1-dodecynyl)-2-thiazolyl]-1,3-propanediol

erythro-N-{1-[4-(1-dodecynyl)-2-thiazolyl]-1,3-dihydroxy-2-propanyl}acetamide(5.8 g), 39 ml 2N sodium hydroxide and ethanol was heated at 60° C.,under nitrogen, for 23 hrs. The reaction mixture was cooled, water wasadded, and the mixture was extracted with chloroform. The extract waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was chromatographed on silicagel eluting with chloroform. The appropriate fractions were collectedand evaporated. A 1.9 g-portion of the residue (4.3 g) wasrecrystallized from ethyl acetate to give 1.6 g (71.0% yield) ofproduct, mp 110°-112° C.

Analysis: Calculated for C₁₈ H₃₀ N₂ O₂ S: 63.87% C 8.93% H 8.28% NFound: 64.02% C 8.95% H 8.23% N

EXAMPLE 190(2S,3S)-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolHydrochloride

A solution of(2S,3S)-2-amino-1-[4-(1-dodecynyl)-2-thienyl-1,3-propanediol maleate(2.8 g) and ethyl acetate was washed two times with 10% aqueous sodiumhydroxide solution and then with water. The organic phase was separated,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was dissolved in ethyl acetate (30ml) and concentrated hydrochloric acid (0.55 ml) was added. The solutionwas concentrated in vacuo, and the residue was recrystallized from2-propanol to give 1.47 g (64%) of product, [α]_(D) ²⁵ =-22° (c. 0.58,ethanol), mp 78° (decomp).

Analysis: Calculated for C₁₉ H₃₂ ClNO₂ S: 61.02% C 8.62% H 3.75% NFound: 61.29% C 8.74% H 3.71% N

EXAMPLE 191(2R,3R)-2-Amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediolHydrochloride

A solution of(2R,3R)-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol maleate(1.3 g) and ethyl acetate was washed two times with 10% aqueous sodiumhydroxide solution and then with water. The organic phase was separated,dried over magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was dissolved in ethyl acetate (30ml), and concentrated hydrochloric acid (0.25 ml) was added. Thesolution was concentrated in vacuo, and the residue was recrystallizedfrom 2-propanol to give 840 mg (78%) of product, [α]_(D) ²⁵ =+27.2° (c.051, ethanol), mp 78° (decomp).

Analysis: Calculated for C₁₉ H₃₂ ClNO₂ S: 61.02% C 8.62% H 3.75% NFound: 60.83% C 8.90% H 3.70% N

EXAMPLE 192erythro-2-Amino-1-[2-(1-dodecynyl)-4-thienyl]-1,3-propanediolHydrochloride

A solution oferythro-N-{1-[2-(1-dodecynyl)-4-thienyl]-1,3-dihydroxy-2-propanyl}acetamide(7.1 g), 2N sodium hydroxide solution (46.5 ml) and ethanol (23 ml) washeated at 60° C., under nitrogen, for 20 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform:methanol:2Nammonium hydroxide solution/950:50:3 to 925:75:4. The appropriatefractions were collected and evaporated. A 3.5 g-portion of the residue(4.84 g) was dissolved in 2-propanol, cooled, and concentratedhydrochloric acid (0.9 ml) was added. The mixture was evaporated,2-propanol was added several times and evaporated, and the residue wasdried under high vacuum to yield 3.7 g (73% yield) of product.

Analysis: Calculated for C₁₉ H₃₂ ClNO₂ S: 61.02% C 8.62% H 3.75% NFound: 60.64% C 8.77% H 3.51% N

EXAMPLE 193erythro-[2-(2-Amino-1,3-dihydroxy-1-propyl)-4-thienyl]-1-dodecanone

A solution oferythro-2-amino-1-[4-(1-dodecynyl)-2-thienyl]-1,3-propanediol (2.00 g),dissolved in tetrahydrofuran (10 ml) was stirred at room temperature as3M sulfuric acid (5 ml), followed by mercury (II) oxide (642 mg) wasadded. The reaction mixture was stirred overnight. The reaction wasrepeated on the same scale, and the two reaction mixtures were combined.The combined reaction mixture was basified with sodium bicarbonatesolution, chloroform was added, and the biphasic mixture was filteredthrough a bed of celite. The filtercake was washed with warm chloroform,and the combined organic phases were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wasflash chromatographed (silica; 90:9:1 dichloromethane:methanol:ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was crystallized from ethyl acetate-petroleum ether to give 2.1g (50%) of product, mp 96°-99° C.

Analysis: Calculated for C₁₉ H₃₃ NO₃ S: 64.19% C 9.36% H 3.94% N Found:64.21% C 9.47% H 3.84% N

EXAMPLE 194N-[1-[4-(1-dodecynyl)-2-thienyl]-3-hydroxy-2-propyl]acetamide

To a solution of diethyl(acetamido)[[4-(1-dodecynyl)-2-thienyl]methyl]propanedioate (12.3 g) indry tetrahydrofuran (100 ml) was added 2M lithiumborohydride/tetrahydrofuran (12.8 ml), and the mixture was stirred at60° C. for 4 hrs. The solution was cooled, quenched with a 50:50:10solution of methanol:water:acetic acid, and extracted with ethylacetate. The organic extracts were evaporated, and the residue waschromatographed on silica gel (9:1 ethyl acetate:dichloromethane). Theappropriate fractions were collected and evaporated. The residue wascrystallized from ether:heptane to give 5.3 g (57%) of product, mp55°-58° C.

Analysis: Calculated for C₂₁ H₃₃ NO₂ S: 69.38% C 9.15% H 3.85% N Found:68.94% C 8.95% N 3.61% N

EXAMPLE 195 2-Amino-3-[4-(1-dodecynyl)-2-thienyl]-1-propanol

To a solution ofN-[1-[4-(1-dodecynyl)-2-thienyl]-3-hydroxy-2-propyl]acetamide (4.6 g) in95% ethanol (30 ml) was added degassed 2N sodium hydroxide solution. Thereaction mixture was stirred at 65° C. overnight. The solution wasdiluted with saturated ammonium chloride solution and extracted withethyl acetate. The organic extracts were evaporated, and the residue wasflashed chromatographed on silica gel (9:1 dichloromethane:methanol).The appropriate fractions were collected and evaporated. The residue wastaken up in ether, an ethereal hydrogen chloride was added, and themixture was stirred at room temperature for 30 mins. The precipitate wascollected and air-dried to give 2.05 g (45.4%) of product, mp 85°-135°C.

Analysis: Calculated for C₁₉ H₃₂ ClNOS: 63.75% C 9.01% H 3.91% N Found:63.66% C 9.21% H 3.76% N

EXAMPLE 196 Diethyl(acetamido)[4-(1-(dodecynyl)-2-thienyl]methyl]propandioate

To a solution of 4-(1-dodecynyl)-2-thiophene methanol (32 g),triethylamine (13.3 g), and dry dichloromethane (250 ml) was addedmethanesulfonyl chloride (10.7 g) over 5 mins, and the mixture wasstirred at room temperatures for 3 hrs. The solution was evaporated, theresidue was taken up in absolute ethanol (100 ml) and was added dropwiseto a solution of diethyl acetamido malonate (29.0 g) and 21 wt % sodiumethoxide (51.5 ml) in absolute ethanol (200 ml). The solution wasstirred, under nitrogen, at 90° C. for 1 hr and then evaporated. Theresidue was taken up in ethyl acetate. The mixture was washed with waterand dilute hydrochloric acid, dried over magnesium sulfate, filtered,and the filtrate was evaporated. The residue was chromatographed (50:1dichloromethane/ethyl acetate). The appropriate fractions were collectedand evaporated to give 27.1 g (49.1%) of product, as an oil.

Analysis: Calculated for C₂₆ H₃₉ NO₅ S: 65.38% C 8.23% H 2.39% N Found:64.94% C 7.88% H 3.23% N

EXAMPLE 197 Ethylerythro-2-acetamido-3-[5-(1-decynyl)-2-benzo[b]thienyl]-3-hydroxypropionate

A solution of 5-(1-decynyl)-2-benzo[b]thiophenecarboxaldehyde (36.8 g)acetamidomalonic acid monoethyl ester (24.5 g), triethylamine (13.1 g),and dry tetrahydrofuran (150 m) was degassed and stirred at roomtemperature, under nitrogen, for five days. Acetamidomalonic acidmonethyl ester (11.7 g) was added, and the solution was degassed andstirred at room temperature under nitrogen, for 2 days. The reactionmixture was evaporated. The residue was flash chromatographed (silica;1:1 ethyl acetate:heptane). The appropriate fractions were collected andevaporated and the residue was crystallized from ether-petroleum ether.Recrystallization of the residue from ethyl acetate:heptane gave 36.7 g(67%) of product, mp 95°-97° C.

Analysis: Calculated for C₂₅ H₃₃ NO₄ S: 67.69% C 7.50% H 3.16% N Found:67.30% C 7.45% H 3.00% N

EXAMPLE 198erythro-N-[1-[5-(1-decynyl)-2-benzo[b]thienyl]-1,3-dihydroxy-2-propyl]acetamide

A solution of ethylerythro-2-acetamido-3-[5-(1-decynyl)-2-benzo[b]thienyl]-3-hydroxypropionate(11.4 g) in dry tetrahydrofuran (100 ml) was stirred at 0° C., undernitrogen, as lithium borohydride (2.0M in tetrahydrofuran) (16.7 ml) wasadded dropwise. The reaction mixture was stirred under a nitrogenatmosphere for three hrs, cooled to 0° C., and quenched by the dropwiseaddition of a 20:20:3 methanol:water:acetic acid solution. The solutionwas diluted with ammonium chloride solution (300 ml) and extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, and the filtrate was evaporated. The residuewas flash chromatographed (silica, 7% methanol:dichloromethane). Theappropriate fractions were collected and evaporated. The residue wasrecrystallized from ethyl acetate:heptane to give 7.3 g (71%) ofproduct, mp 130°-132° C.

Analysis: Calculated for C₂₃ H₃₅ NO₃ S: 68.11% C 8.70% H 3.45% N Found:67.89% C 8.82% H 3.47% N

EXAMPLE 199erythro-2-Amino-1-[5-(1-decynyl)-2-benzo[b]thienyl-1,3-propanediol

A solution oferythro-N-[1-[5-(1-decynyl)-2-benzo[b]thienyl]-1,3-dihydroxy-2-propyl]acetamide(10.5 g), 2N sodium hydroxide solution (100 ml) and 95% ethanol (75 ml)was stirred at 50° C. overnight. The reaction mixture was cooled to roomtemperature, diluted with ammonium chloride solution (300 ml) andextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed (silica; 90:9:1dichloromethane:methanol:ammonium hydroxide). The appropriate fractionswere collected and evaporated. The residue was recrystallized from ethylacetate to give 5.7 g of product, mp 146°-149° C.

Analysis: Calculated for C₂₁ H₂₉ NO₂ S: 70.16% C 8.13% H 3.90% N Found:69.88% C 8.35% H 3.75% N

EXAMPLE 200erythro-N-[1-[5-(1-decyl)-2-benzo[b]thienyl-1,3-dihydroxy-2-propyl]acetamide

A mixture oferythro-N-[1-[5-(1-decynyl)-2-benzo[b]thienyl]-1,3-dihydroxypropyl]acetamido(6.00 g) and 5% palladium-on-carbon (600 mg) in absolute ethanol (200ml) was shaken under 50 psi of hydrogen overnight. The catalyst wasfiltered and washed with ethanol. The filtrate was evaporated, and theresidue was recrystallized from ethyl acetate to give 5.0 g (83%) ofproduct, mp 115°-117° C.

Analysis: Calculated for C₂₃ H₃₅ NO₃ S: 68.11% C 8.70% H 3.45% N Found:67.89% C 8.82% H 3.47% N

EXAMPLE 201erythro-2-Amino-1-[5-(1-decyl)-2-benzo[b]thienyl]-1,3-propanediol

A solution oferythro-N-[1-[5-(1-decyl)-2-benzo[b]thienyl]-1,3-dihydroxy-2-propyl]acetamide(3.90 g), 2N sodium hydroxide solution (100 ml), and 95% ethanol (75 ml)was stirred at 50° C. overnight. The reaction mixture was cooled to roomtemperature, diluted with ammonium chloride solution (300 ml) andextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was flash chromatographed (silica,90:9:1/dichloromethane:methanol:ammonium hydroxide). The appropriatefractions were collected and evaporated. The residue was recrystallizedfrom ethyl acetate and then ethanol to give 2.3 g of product, mp138°-139° C.

Analysis: Calculated for C₂₂ H₃₃ NO₂ S: 69.38% C 9.155H 3.85% N Found:69.36% C 9.36% H 3.83% N

EXAMPLE 202 Ethylerythro-2-acetamido-3-[6-(1-decynyl)-2-quinolinyl]-3-hydroxypropionate

A solution of 6-(1-decynyl)-2-quinolinecarboxaldehyde (21.4),acetamidomalonic acid monoethyl ester(13.8 g), and triethylamine (8.1 g)in dry tetrahydrofuran (140 ml) was stirred overnight, under nitrogen,for 3 days. The reaction mixture was evaporated, ethyl acetate wasadded, and the solution was washed with saturated sodium bicarbonate andsodium chloride solutions. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was chromatographed on silica gel, eluting with heptane:ethylacetate/4:1 to 1:2. The appropriate fractions were collected andevaporated. A 11.45 g-portion of the residue (22.7 g) was recrystallizedfrom hexane:ethyl acetate/9:1 to give 9.9 g (61.5%) of product, mp86°-88° C.

Analysis: Calculated for C₂₆ H₃₄ N₂ O₄ : 71.21% C 7.81% H 6.39% N Found:71.17% C 7.93% H 6.43% N

EXAMPLE 203erythro-2-Amino-1-[6-(1-decynyl)-2-quinolinyl]-1,3-propanediol Maleate

A solution oferythro-N-{1-[6-(1-decynyl-2-quinolinyl]-1,3-dihydroxy-2-propanyl}acetamide(4.9 g), 2N sodium hydroxide solution (31 ml), and ethanol (30 ml) washeated at 60° C., under nitrogen, for 24 hrs. The reaction mixture wascooled, water was added, and the mixture was extracted with chloroform.The extract was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was evaporated. The residue waschromatographed twice on silica gel eluting with chloroform:methanol:2Nammonium hydroxide/950:50:3 to 925:75:4. The appropriate fractions werecollected and evaporated each time. The residue was dissolved in ethylacetate, maleic acid (0.20 g) was added, and the solution was chilled.The precipitate was collected to yield 0.65 g (11%) of product, mp119°-120° C.

Analysis: Calculated for C₂₆ H₃₄ N₂ O₆ : 66.36% C 7.28% H 5.95% N Found:66.37% C 7.42% H 5.92% N

EXAMPLE 204erythro-N-{1-[6-(1-Decynyl)-2-quinolinyl]-1,3-dihydroxy-2-propanyl}acetamide

To a solution oferythro-2-acetamido-3-[6-(1-decynyl)-2-quinolinyl]-3-hydroxypropionate(12.9 g) in dry tetrahydrofuran (125 ml) was added slowly 2M lithiumborohydride/tetrahydrofuran (12.5 ml) at 5° C., under nitrogen, at roomtemperature, with stirring overnight. The reaction mixture was stirredovernight, chilled, and methanol:water/1:1 (25 ml) was added slowly,followed by glacial acetic acid (1.6 ml) in methanol:water/1:1 (25 ml).The solution was stirred at room temperature for 1 hr, evaporated, andthe residue was azeotroped with methanol. Saturated sodium bicarbonatesolution was added to the residue until pH 8, and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was flash chromatographed on silica gel,eluting with ethyl acetate:methanol (1-5%). The appropriate fractionswere collected and evaporated. A 4.4 g-portion of the residue (8.5 g)was recrystallized from ethyl acetate to give 2.45 g (40.5%) of product,mp 145°-147° C.

Analysis: Calculated for C₂₄ H₃₂ N₂ O₃ : 72.70% C 8.13% H 7.06% N Found:72.30% C 8.13% H 7.12% N

EXAMPLE 205 Ethylerythro-2-acetamido-3-hydroxy-[1-(4-methylphenylsulfonyl)-5-(1-decynyl)-3-(1H)-indolyl]propionate

To a solution containing1-(4-methylphenylsulfonyl)-5-(1-decynyl)-1H-indole-3-carboxaldehyde(11.6 g) and acetamidomalonic acid monethyl ester (4.8 g) in drytetrahydrofuran (150 ml) was added 1.5 equivalents of triethylamine (3.7ml). The mixture was stirred at room temperature overnight. Additional0.5 equivalents of acetamidomalonic acid monethyl ester (total 19.5 g)were added every morning for 8 additional days. The reaction mixture wasevaporated and the residue flash chromatographed on silica gel (9:1dichloromethane:ethyl acetate). The appropriate fractions were collectedand evaporated. The residue was crystallized from ether to give 9.3 g(62.0%) of product, mp 56°-58° C.

Analysis: Calculated for C₂₆ H₂₉ NO₃ S: 66.18% C 6.94% H 4.80% N Found:61.18% C 7.14% H 4.74% N

EXAMPLE 206erythro-N-[1-[5-(1-Decynyl)-1-(4-methylphenylsulfonyl)-3-(1H)-indolyl]-1,3-dihydroxy-2-proponylacetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-[1-(4-methylphenylsulfonyl)-5-(1-decynyl)-3-(1H)-indolyl]propionate(21.2 g) in dry tetrahydrofuran (150 ml) was added 2M lithiumborohydride (23.1 ml) over 10 mins, and the mixture was then stirred atroom temperature for 3 hrs. The reaction mixture was quenched withmethanol:water:acetic acid 5:5:1 and extracted with ethyl acetate. Theresidue was flash chromatographed on silica gel (ethyl acetate to 20:1ethyl acetate:methanol). The appropriate fractions were collected andevaporated. The residue was recrystallized from ethyl acetate:heptane togive 8.7 g (45.3%) of product, mp 116°-118° C.

Analysis: Calculated for C₃₁ H₄₀ N₂ O₅ S: 66.89% C 7.11% H 5.20% NFound: 66.47% C 7.22% H 5.14% N

EXAMPLE 207erythro-N-{1-[3-(1-Dodecynyl)-2-fluorophenyl]-1,3-dihydroxy-2-propanyl}acetamide

A solution oferythro-N-{1,3-diacetyloxy-1-[3-(1-dodecynyl)-2-fluorophenyl]-2-propanyl}acetamide(14.7 g), 25% sodium hydroxide solution (50 ml), and ethanol (125 ml)was heated at 70° C., under nitrogen, for 3 hrs. The reaction mixturewas cooled, water was added, and the mixture was extracted with ethylacetate. The extract was washed with sodium chloride solution, driedover anhydrous mangensium sulfate, filtered, and the filtrate wasevaporated. The residue was chromatographed on silica gel eluting withchloroform:methanol: 2N ammonium hydroxide solution/950:50:3. Theappropriate fractions were collected and evaporated to give 7.8 g (64%)of product. Recrystallization from heptane:ethyl acetate/1:1 gave theanalytical sample, mp 77°-79° C.

Analysis: Calculated for C₂₃ H₃₄ FNO₃ : 70.56% C 8.75% H 3.58% N Found:70.92% C 8.90% H 3.53% N

EXAMPLE 208erythro-[3-(2-Amino-1,3-dihydroxy-1-propyl)phenyl]-1-dodecanoneHydrochloride

To a solution oferythro-2-amino-1-[3-(1-dodecynyl)phenyl]-1,3-propanediol intetrahydrofuran (150 ml) was added mercury (II) oxide (1.9 g) in asingle portion, followed by 3N sulfuric acid (100 ml). The mixture wasstirred at room temperature for 4 days, diluted with ethyl acetate andwashed with 10% aqueous sodium hydroxide. The aqueous phase wasextracted with chloroform and the organic phases were combined, driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was diluted with ethyl acetate (100ml) and concentrated hydrochloric acid (0.5 ml) was added, withstirring. The precipitate was filtered and recrystallized from ethylacetate:methanol/10:1 to give 1.65 g (22%) of product, mp 120° C.(decomp.).

Analysis: Calculated for C₂₁ H₃₆ ClNO₃ : 65.35% C 9.40% H 3.63% N Found:65.35% C 9.54% H 3.55% N

EXAMPLE 209 Ethylerythro-2-acetamido-3-hydroxy-3-(3-acetoxyphenyl)propionate

To a solution of 3-acetoxybenzaldehyde (40.5 g) in tetrahydrofuran (200ml) at room temperature was added acetamido malonic acid monoethylester(49.2 g), followed by triethylamine (36 ml). The mixture was stirred at48 hrs at room temperature, at the end of which time, an additional 0.5equivalents of both acetamido malonic acid monoethylester andtriethylamine were added. The reaction mixture was stirred for anadditional 48 hrs and another 0.5 equivalents of acetamido malonic acidmonoethylester and triethylamine were added. The reaction mixture wasstirred for an additional 72 hrs, concentrated to 1/3 of its originalvolume, diluted with ethyl acetate and washed with saturated aqueoussodium bicarbonate, and then with water. The organic phase wasseparated, dried over anhydrous magnesium sulfate, filtered, and thefiltrate concentrated in vacuo. The appropriate fractions were collectedand evaporated. The residue was flash chromatographed over silica gel(eluted with ethyl acetate:heptane/2:1). The appropriate fractions werecollected and concentrated. The residue was recrystallized from ethylacetate:heptane/5:1 to give 32.6 g (43%) of product, mp 119°-120° C.

Analysis: Calculated for C₁₅ H₁₉ O₆ N: 58.25% C 6.19% H 4.53% N Found:58.15% C 6.11% H 4.36% N

EXAMPLE 210erythro-N-[1,3-Dihydroxy-1-(3-undecyloxyphenyl)-2-propanyl]acetamide

To a solution of ethylerythro-2-acetamido-3-hydroxy-3-(3-acetoxyphenyl)propionate (15 g) intetrahydrofuran (200 ml) at 0° C. was added lithium borohydride (2.0M,tetrahydrofuran) (48.4 ml). The solution was allowed to warm to roomtemperature and stirred for 48 hrs. The reaction mixture was quenchedwith methanol (50 ml), diluted with water (500 ml) and extracted withtwo 500 ml-portions of ethyl acetate. The aqueous phase was concentratedin vacuo. The residue was diluted with water (50 mi) and acetone (300ml), and the precipitate was collected. The filtrate was concentrated invacuo, and the residue was flash chromatographed over silica gel (elutedwith chloroform:methanol/4:1). The appropriate fractions were collectedand evaporated to give 5.24 g (48%) oferythro-N-[1,3-dihydroxy-1-(3-hydroxyphenyl)-α-propanyl]acetamide aswhite solid.

To a solution oferythro-N-[1,3-dihydroxy-1-(3-hydroxyphenyl)-α-propanyl]acetamido (4.33g) in dimethylformamide (40 ml) was added cesium carbonate (6.8 g)followed by bromoundecane (4.54 g). The mixture was stirred at roomtemperature for 48 hrs. The mixture was partitioned betweendichloromethane (500 ml) and water (200 ml). The aqueous phase wasextracted with dichloromethane, and the organic phases were combined,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The residue was recrystallized from ethyl acetateto give 5.0 g (69%) of the product.

Analysis: Calculated for C₂₂ H₃₇ NO₄ : 69.62% C 9.83% H 3.69% N Found:69.18% C 9.96% H 3.64% N

EXAMPLE 211 erythro-2-Amino-1-[3-(1-undecyloxy)phenyl]-1,3-propanediolHydrochloride

To a solution oferythro-N-[1,3-dihydroxy-1-(3-undecyloxyphenyl)-2-propanyl]acetamide inethanol (50 ml) was added potassium hydroxide (1.68 g) in one portion.The mixture was warmed to 70° C. and stirred overnight. The reactionmixture was allowed to cool to room temperature, concentrated in vacuo,and the concentrate was diluted with ethyl acetate and washed withwater. The aqueous phase was extracted with ethyl acetate, and theorganic phases were combined, dried over magnesium sulfate, filtered,and the filtrate was concentrated in vacuo. The residue was dissolved inethyl acetate (100 ml) and concentrated hydrochloric acid (1 ml) wasadded dropwise, with stirring. The precipitate was collected andrecrystallized from ethyl acetate to give 1.57 g of product, mp 92°-93°C. (decomp).

Analysis: Calculated for C₂₀ H₃₆ ClNO₃ : 64.24% C 9.70% H 3.75% N Found:64.23% C 9.74% H 3.67% N

EXAMPLE 212 4-(1-Dodecynyl)-2-thiazolecarboxaldehyde

A solution of 4-bromo-2-thiazolecarboxaldehyde (14.8 g), 1-dodecyne(14.1 g), and triethylamine (23.5 g) in dry tetrahydrofuran (85 m) waschilled to 5° C. and degassed under nitrogen.bis(Triphenylphosphine)palladium (II) chloride (0.54 g) and copper (I)iodide (0.07 g) were added to the mixture, which was degassed, andstirred, under nitrogen, at room temperature for 2.5 hrs. The reactionmixture was heated at 40° C. for 7 hrs, during which time additionalamounts of 1-dodecyne (3.9 g), bis(triphenylphosphine)palladium (II)chloride (0.11 g), and copper (I) iodide (0.02 g) were added. Themixture was cooled to room temperature, the precipitate was collected,and the filter cake was washed with ethyl acetate. The filtrate wasdiluted with ethyl acetate (300 ml). Water was added in portions, andthe organic layer was washed with brine, dried over magnesium sulfate,filtered, and the filtrate was concentrated. The residue waschromatographed on silica gel, eluting with heptane to heptane:1% ethylacetate. A portion (1.05 g) of the residue was rechromatographed,eluting with hexane:(0.3 to 1%) ethyl acetate. The appropriate fractionswere collected and evaporated to yield 0.79 g (76.5% yield) of product,mp 25.5°-26° C.

Analysis: Calculated for C₁₆ H₂₃ NOS: 69.27% C 8.36% H 5.05% N Found:69.51% C 8.65% H 4.94% N

EXAMPLE 213 5-(1-decynyl)-2-benzo[b]thiophenecarboxaldehyde

To a solution of 5-(1-decynyl)benzo[b]thiophene (20.0 g) in dry ether(150 ml), under nitrogen, was added n-butyllithium (2.5M in hexanes)(32.6 ml) dropwise, with stirring at room temperature. The solution wasstirred at room temperature, under nitrogen, for 2.5 hrs and then cooledto -60° C. A solution of dry dimethylformamide (5.95 g) in dry ether (15ml) was added dropwise, and the reaction mixture was allow to warm toroom temperature. The reaction mixture was quenched with ammoniumchloride solution and the layers separated. The aqueous phase wasextracted with ether, the organic extracts combined, dried overanhydrous sodium sulfate, filtered, and the filtrate was evaporated. Theresidue was flash chromatographed (silica: 3-4%, ethyl acetate:heptane).The appropriate fractions were collected and evaporated. The residue wasrecrystallized from heptane to give 11.5 g (52.0%) of product, mp45°-47° C.

Analysis: Calculated for C₁₉ H₂₂ OS: 76.47% C 7.43% H Found: 76.63% C7.36% H

EXAMPLE 214 6-(1-Decynyl)-2-quinolinecarboxaldehyde

A solution of 6-bromo-2-quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) waschilled to 5° C. and degassed, under nitrogen.bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I)iodide (0.08 g) were added to the reaction mixture, which was degassedand stirred under nitrogen at room temperature for 30 mins, and thenheated at 40° C. for 19 hrs. The mixture was cooled to room temperature,the precipitate was filtered, and the filter cake was washed with ethylacetate, and the filtrate was evaporated. The residue was dissolved inethyl acetate, washed with water and brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was chromatographed on silica gel, eluting with heptane toheptane:2% ethyl acetate. The appropriate fractions were collected andevaporated. A 2 g-portion of the residue (23.4 g) was chromatographed,eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product,mp 46.5°-47.5° C.

Analysis: Calculated for C₂₀ H₂₃ NO: 81.87% C 7.90% H 4.77% N Found:81.51% C 7.94% H 4.82% N

EXAMPLE 2151-(4-Methylphenylsulfonyl)-5-(1-dodecynyl)indole-3-carboxaldehyde

To a degassed mixture of1-(4-methylphenylsulfonyl)-5-bromoindole-3-carboxaldehyde (36.9 g),1-decyne (16.8 g), in dry triethylamine (200 ml) and dry tetrahydrofuran(150 ml) was added, 1 mole percent of copper (II) iodide and 2 molepercent of bis(triphenylphosphine)palladium (II) chloride. The reactionmixture was stirred at 65° C. for 7 days. The solution was evaporated,and the residue was flash chromatographed (silica gel:4:1,dichloromethane:heptane). The appropriate fractions were collected andevaporated. The residue was recrystallized from hexane to give 23.1 g(50.8%) of product, mp 84°-86° C.

Analysis: Calculated for C₂₆ H₂₉ NO₃ S: 71.69% C 6.71% H 3.22% N Found:71.69% C 6.75% H 3.21% N

EXAMPLE 216 5-(1-Decynyl)benzo[b]thiophene

To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g),triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen,was added bis(triphenylphosphine)palladium (II) chloride (1.65 g)followed by copper (I) iodide (0.233 g) with stirring, at roomtemperature. The reaction mixture was covered with foil and stirred atreflux, under nitrogen, over the weekend. Additionalbis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper(I) iodide were added, and the reaction mixture was stirred at refluxfor three days, cooled, filtered through a bed of celite and the filtercake was washed with ether. The residue was flash chromatographed(silica, 1% ethyl acetate-heptane). The appropriate fractions werecollected and evaporated to give 56.3 g (89%) of product.

EXAMPLE 217 5-Bromoindole-3-carboxaldehyde

To a solution of phosphorous oxychloride (26.1 g) and drydimethylformamide (50.9 ml), cooled to -10° C., was added 5-bromoindole(30 g) in portions. The reaction mixture was stirred at 10° C. for 1 hr.and at 35° C. for 1 hr. Ice (100 g) was added to the reaction mixture,followed by sodium hydroxide solution (50 ml). The mixture was heated ona steam bath for one-half hour. The precipitate was collected andrecrystallized from ethanol to give 35.5 g (97.7%) of product.

EXAMPLE 218 5-Bromo-1-(4-methyphenylsulfonyl)indole-3-carboxaldehyde

To a solution of 5-bromoindole-3-carboxaldehyde (10 g) in drytetrahydrofuran (75 ml), cooled to -78° C., was added with 2M lithiumdiisopropylamide/tetrahydrofuran (22.5 ml). After 30 min., the mixturewas treated with a solution of tosyl chloride (9.5 g) in drytetrahydrofuran (75 ml). The mixture was allowed to warm to roomtemperature overnight and evaporated. The residue was dissolved indimethylformamide, filtered, and the filtrate was diluted with water.The precipitate was collected and recrystallized from ethanol to give 42g (25%) of product.

EXAMPLE 219 1-(7-Bromo)naphthoyl-N,N-diethylcarbamate

To a solution of 7-bromo-1-naphthol (35.0 g) in dry pyridine (60 ml) wasadded N,N-diethylcarbamylchloride (25.6 ml) in one portion. The solutionwas warmed to 80° C. overnight. The reaction mixture was allowed to coolto room temperature and poured over ice water. The mixture was extractedwith ethyl acetate, and the organic phase was washed with 5%hydrochloric acid and water. The organic phase was separated, dried overanhydrous magnesium sulfate, filtered, and the filtrate concentrated invacuo. The residue was flash chromatographed over silica gel (elutedwith ethyl acetate:hexane/1:5). The appropriate fractions were collectedand concentrated. The residue was crystallized from diethylether:hexane/1:10 to afford 15.5 g (31%) of product, mp 74°-76° C.

Analysis: Calculated for C₁₅ H₁₆ BrNO₂ : 55.92% C 5.01% H 4.35% N Found:55.60% C 5.04% H 4.21% N

EXAMPLE 220 erythro-2-Amino-1-[3-(1-Undecyloxy)phenyl]-1,3-propanediolMaleate

erythro-2-Amino-1-[3-(1-undecyloxy)phenyl]-1,3-propanediol hydrochloride(2.15 g) was neutralized in 10% aqueous sodium hydroxide, and themixture was extracted with ethyl acetate. The organic phase wetsseparated, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated in vacuo. The residue was dissolved in ethylacetate (15 ml) and treated with 1 eq of maleic acid. The solution wasconcentrated, and the residue was recrystallized from ethyl acetate toafford 0.85 g (33%) of product, mp 120°-122° C.

Analysis: Calculated for C₂₄ H₃₉ NO₇ : 63.55% C 8.67% H 3.09% N Found:63.71% C 8.65% H 3.01% N

EXAMPLE 221erythro-1-[3-(2-Amino-1,3-dihydroxy-1-propanyl)-2-fluoro-1-phenyl]-1-dodecanoneHydrochloride

To a solution oferythro-2-amino-1-[3-(1-dodecynyl)-2-fluoro-1-phenyl]-1,3-propanediol(7.56 g) dissolved in tetrahydrofuran (120 ml) was addedmercuric(II)oxide (2.3 g) and 3M sulfuric acid (72 ml). The reactionmixture was stirred for six days, ethyl acetate was added, and themixture was basified with 10% sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the extracts were washed with sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was evaporated. The residue was fractionally recrystallizedto give 2.4 g (30%) of product free base. A portion was recrystallizedfrom ethyl acetate:10% ethanol with 1 eq. of hydrochloric acid to giveproduct, mp 135°-137° C.

Analysis: Calculated for C₂₁ H₃₅ ClFNO₃ : 62.44% C 8.73% H 3.47% NFound: 62.51% C 8.78% H 3.41% N

EXAMPLE 222erythro-1-[3-(2-Amino-1,3-dihydroxy-1-propanyl-2-fluoro-1-phenyl]-1-dodecanoneMaleate

To a solution oferythro-2-amino-1-[3-(1-dodecynyl)-2-fluoro-1-phenyl]-1,3-propanediol(7.56 g) dissolved in tetrahydrofuran (120 ml) was addedmercuric(II)oxide (2.3 g) and 3M sulfuric acid (72 ml). The reactionmixture was stirred for six days, ethyl acetate was added, and themixture was basified with 10% sodium hydroxide solution. The reactionmixture was extracted with ethyl acetate, and the extracts were washedwith sodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and the filtrate was evaporated. The residue was fractionallyrecrystallized to give 2.4 g (30%) of product free base. A portion wasrecrystallized from ethyl acetate:1% ethanol with 1 eq. of maleic acidto give product, mp 114°-116° C.

Analysis: Calculated for C₂₅ H₃₈ FNO₇ : 62.09% C 7.92% H 2.90% N Found:62.14% C 8.07% H 2.85% N

EXAMPLE 223erythro-1-[5-(2-Amino-1,3-dihydroxy-1-propanyl)-2-thienyl]-1-dodecanone

To a solution oferythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (10.1 g)dissolved in tetrahydrofuran (150 ml), was added mercuric(II)oxide (3.3g) and 3M sulfuric acid (100 ml). The reaction mixture was stirredovernight, ethyl acetate was added, and the mixture was basified with10% sodium hydroxide solution. The reaction mixture was extracted withethyl acetate, and the extracts were washed with sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was chromatographed on silica gel,eluting with chloroform:methanol:2N ammonium hydroxide/950:50:3. Theappropriate fractions were collected and evaporated. The residue wasdried to give 5.5 g (51%) of product, mp 121°-125° C.

Analysis: Calculated for C₁₉ H₃₃ NO₃₃ S: 64.19% C 9.36% H 3.94% N Found:64.33% C 9.58% H 3.86% N

EXAMPLE 224erythro-1-[5-(2-Amino-1,3-dihydroxy-1-propanyl)-2-thienyl]-1-dodecanoneMaleate

To a solution of erythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (10.1 g) dissolved in tetrahydrofuran (150 ml) wasadded mercuric(II)oxide (3.3 g) and 3M sulfuric acid (100 ml). Thereaction mixture was stirred overnight, ethyl acetate was added, and themixture was basified with 10% sodium hydroxide solution. The reactionmixture was extracted with ethyl acetate, and the extracts were washedwith sodium chloride solution, dried over anhydrous magnesium sulfate,filtered, and the filtrate was evaporated. The residue waschromatographed on silica gel, eluting with chloroform:methanol:2Nammonium hydroxide/950:50:3. The appropriate fractions were collectedand evaporated. The residue was was recrystallized with 1 eq. of maleicacid from ethyl acetate to give 2.6 g (51%) of product, mp 133°-135° C.

Analysis: Calculated for C₂₃ H₃₇ NO₇ S: 58.58% C 7.91% H 2.97% N Found:58.78% C 7.95% H 3.00% N

EXAMPLE 225erythro-1-[5-(2-Amino-1,3-dihydroxy-1-propanyl)-2-thienyl]-1-dodecanoneHydrochloride

To a solution oferythro-2-amino-1-[5-(1-dodecynyl)-2-thienyl]-1,3-propanediol (10.1 g)dissolved in tetrahydrofuran (150 ml) was added mercuric(II)oxide (3.3g) and 3M sulfuric acid (100 ml). The reaction mixture was stirredovernight, ethyl acetate was added, and the mixture was basified with10% sodium hydroxide solution. The reaction mixture was extracted withethyl acetate, and the extracts were washed with sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered and thefiltrate was evaporated. The residue was chromatographed on silica gel,eluting with chloroform:methanol:2N ammonium hydroxide/950:50:3. Theappropriate fractions were collected and evaporated. The residue wasdried and recrystallized with 1 eq. of hydrochloric acid from ethylacetate to give 1.8 g (47%) of product, mp 140°-143° C.

Analysis: Calculated for C₁₉ H₃₄ ClNO₃ S: 58.22% C 8.74% H 3.57% NFound: 58.38% C 9.06% H 3.58% N

EXAMPLE 226erythro-1-[5-(2-Ethylamino-1,3-dihyroxy-1-propanyl)-2-thienyl]-dodecanoneHydrochloride

To a solution oferythro-1-[5-(1-dodecynyl)-2-thienyl]-2-ethylamino-1,3-propan ediol(4.75 g) dissolved in tetrahydrofuran (60 ml) was addedmercuric(II)oxide (1.4 g), and 3M sulfuric acid (43 ml). The reactionmixture stirred overnight, ethyl acetate was added, and the mixture wasbasified with 10% sodium hydroxide solution. The reaction mixture wasextracted with ethyl acetate, and the extracts were washed with sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andthe filtrate was evaporated. The residue was chromatographed on silicagel, eluting with chloroform:methanol:2N ammonium hydroxide/950:50:3.The appropriate fractions were collected and evaporated. The residue wasdried and recrystallized from ethyl acetate:4% ethanol with 1 eq. ofhydrochloric acid to give 1.4 g (42%) of product, mp 103°-105° C.

Analysis: Calculated for C₂₁ H₃₈ ClNO₃ S: 60.05% C 9.12% H 3.33% NFound: 60.41% C 9.50% H 3.29% N

EXAMPLE 227erythro-1-[5-(2-Ethylamino-1,3-dihydroxy-1-propanyl)-2-thienyl]-1-dodecanoneMaleate

To a solution oferythro-1-[5-(1-dodecynyl)-2-thienyl]-2-ethylamino-1,3-propanediol (4.75g), dissolved in tetrahydrofuran (60 ml), was added mercuric(II)oxide(1.4 g) and 3M sulfuric acid (43 ml). The reaction mixture was stirredovernight, ethyl acetate was added, and the mixture was basified with10% sodium hydroxide solution. The reaction mixture was extracted withethyl acetate, and the extracts were washed with sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated. The residue was chromatographed on silica gel,eluting with chloroform:methanol:2N ammonium hydroxide/950:50:3. Theappropriate fractions were collected and evaporated and dried to give2.7 g of product free base. A portion (1.06 g) of product free base wasrecrystallized from ethyl acetate:2% ethanol with 1 eq. of maleic acidto give 1.1 g (44.5%) of product, mp 128°-130° C.

Analysis: Calculated for C₂₅ H₄₁ NO₇ S: 60.10% C 8.27% H 2.80% N Found:60.39% C 8.52% H 2.77% N

EXAMPLE 228(2S,3R)-2-Amino-3-[7-(1-decynyl)-1-hydroxy-2-naphthalenyl]-3-methoxy-1-propanolMaleate

To a solution of 1-(7-bromo)naphthoyl-N,N-diethylcarbamate (28 g) andtetrahydrofuran (100 ml) was added of 1-decyne (15.6 g), followed bybistriphenylphosphine palladium(II) chloride (1.2 g), copper(I) iodide(165 mg), and triethyl amine (61 ml). The solution was warmed to 50° C.and stirred for 2 hrs. The slurry was filtered, the filtercake waswashed with ethyl acetate, and the filtrate was washed with water,followed by brine. The organic phase was separate, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was flash chromatographed over silica gel (eluted with ethylacetate:heptane/1:8). The appropriate fractions were collected andevaporated to afford 31.5 g (95%) of1-[7-(1-decynyl)naphthoyl]-N,N-diethylcarbamate.

To a solution of 1-[7-(1-decynyl)naphthoyl]-N,N-diethylcarbamate (7.58g) and tetraethylenediamine (3.3 ml) in tetrahydrofuran (50 ml) at -78°C. was slowly added s-butyllithium (1.3M in cyclohexane) (17 ml) over 15mins. The solution was stirred for ten mins and a solution of1,1-dimethylethyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate(5.0 g) in tetrahydrofuran (20 ml) was added. The solution was stirredfor 20 mins at -78° C., quenched with water, and extracted with ethylacetate. The organic phase was separated, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. The residue wasflashed chromatographed over silica gel (eluted with ethylacetate:heptane/1:4). The appropriate fractions were collected andevaporated to give 6.57 g (54%) of mixture of erythro- and threo aldols.An identical reaction was carried out to afford and additional 5.43 g ofthis product.

To a solution of the aldols (11.5 g) in methanol (100 ml) at roomtemperature was added 3.6 g of p-toluenesulfonic acid. The mixture wasstirred at room temperature for 1 hr, whereupon an additional equivalentof p-toluenesulfuric acid was added. The solution was stirred overnight,the mixture was diluted with ethyl acetate, and the solution was washedwith water and brine. The organic phase was separated, dried overanhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was flash chromatographed over silica gel(eluted with chloroform:methanol/8:1). The appropriate fractions werecollected and evaporated to afford 2.3 g of an aminodiolcarbamate as asingle diastereomer and 4.3 g of an aminodiolcarbamate as a mixture ofdiastereomers. A second reaction afforded 1.92 g of pure amino diolcarbamate.

To a solution of the aminodiolcarbamates (2.31 g) in methanol (40 ml) atroom temperature was added potassium hydroxide (1.37 g). The solutionwas warmed to 50° C. and stirred for 30 mins. The solution was allowedto cool to room temperature, diluted with ethyl acetate and washed with5% hydrochloric acid, followed by saturated sodium bicarbonate andbrine. The organic phase was separated, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. The residue wasflash chromatographed over silica gel (eluted withchloroform:methanol/8:1). The appropriate fractions were collected andconcentrated to afford 722 mg of the product free base. A secondreaction afforded 510 mg of additional product.

To a solution of product free base (1.2 g) in ethyl acetate (10 ml) wasadded maleic acid (363 mg). The solution was concentrated in vacuo, andthe residue recrystallized twice from ethyl acetate to afford 1.32 g(11% overall) of product, mp 134°-135° C., [α]p²³ =+58.7° (c. 0.64,ethanol.

Analysis: Calculated for C₂₈ H₃₇ NO₇ : 67.32% C 7.46% H 2.80% N Found:67.37% C 7.61% H 2.76% N ##STR61##

We claim:
 1. A method of relieving memory dysfunction in mammalscomprising administering to a mammal requiring memory dysfunctionrelief, a memory dysfunction relieving effective amount of a compound ofthe formula

    RCH(OR.sup.1)CH(NR.sup.2 R.sup.3)R.sup.4 or RCH.sub.2 CR.sup.35 (NR.sup.2 R.sup.3)R.sup.4 wherein R is ##STR62## wherein R.sup.5 is CH.sub.3 (CH.sub.2).sub.m C.tbd.C wherein m is 3 to 15 and X is hydrogen, hydroxy, loweralkyl, loweralkoxy, halogen or trifluoromethyl, or ##STR63## wherein R.sup.23 is loweralkyl; R.sup.1 is hydrogen, loweralkyl, ##STR64## wherein R.sup.24 is loweralkyl or ##STR65## wherein R.sup.6 is hydrogen, loweralkyl, loweralkoxy, N(R.sup.21).sub.2 wherein R.sup.21 is hydrogen, loweralkyl or ##STR66## R.sup.2 is hydrogen or loweralkyl; R.sup.3 is hydrogen, loweralkyl or ##STR67## wherein R.sup.6 is as above or NHR.sup.27 wherein R.sup.27 is loweralkyl; R.sup.4 is ##STR68## wherein R.sup.7 is hydrogen, loweralkyl or C(R.sup.25).sup.2 OR.sup.8 wherein R.sup.8 is hydrogen, loweralkyl or ##STR69## wherein R.sup.6 is as above and R.sup.25 is hydrogen or loweralkyl; the optical isomers thereof, or the pharmaceutically acceptable salts thereof.